Metabolism of Vitamins

Metabolism of vitamins

Arash Azarfar

Lorestan University McDowell, L. R. 2000. Vitamins in Animal and Human Nutrition, 2nd ed.,

Iowa State University Press, Ames, IA Bender, 2003, Nutritional biochemistry of vitamins, 2nd edition, Cambridge, UK. Berdanier,C.D. 2000, Advanced nutrition micronutrients, CRC Press.

Lorestan University ویتامین ها Vitamins

Vitamins are substances which are involved in: • Gene expression (A, D, B1, B12) • Structural role in visual pigments (A as retinol) • As antioxidant (A, E, C) • As enzyme cofactors (B group, K)

The first identified vitamin was identified by Funk(1921). ‘Vital amine’ or ;vitamine’ ‘Vitamin’ Lorestan University ویتامین ها : Vitamin : fat soluble type Names Functions

A, retinoic acid, retinol, Vision, retinaldehyde Maintenance of epithelial cells Reproduction, Growth, D, Phosphocalcium metabolism, cholecalciferol,ergocalciferol Growth, Reproduction, E, α-, β-, γ-, tocopherols Biological antioxidant, phospholipids' membrane stability, Immunomodulation K, menadion, phylloquinone, Cofactor in coagulation menaquinone

Lorestan University ویتامین ها Vitamins: water soluble Names Functions Thiamin, B1, aneurin Coenzyme in oxidative Decarboxylation, Role in neurophysiology Ribofelavin, B2 Intermediary in the transfer of electrons in biological oxidation- reduction reactions Niacin , B3, nicotinamide, pp Constituent of coenzyme NAD factor and NADP in carbohydrate, protein and fat metabolism Panthotenic acid, B5 Coenzyme A precursor B6, pyridoxine, pyridoxal, Amino acid metabolism, pyridoxamine Formation of biogenic amines

Lorestan University Vitamins: water soluble Names Functions Biotin , B7, H, coenzyme R Coenzyme in carbohydrate, protein and fat metabolism Folate, B9, B11, Bc, M , folic acid Growth,Haematopoiesis, Maintenance of immune system B12, Integrity of nervous system, cyanocobalamin,aquacobalamin Growth, Haematopoiesis Choline Synthesis of acetylcholine,component of phospholipids, metyle radical donor, lipotrophic factor Lipoic acid, thioctic acid C, ascorbic acid, dehydroascorbic Collagen biosynthesis, Transfer of acid electrons, Oxidation reaction

Lorestan University Thiamin, B1

Lorestan University Overview, History of B1

In 1630, Jacobus Bonitus, first record of disease in Java named Beriberi. In 1894, Takaki, a surgeon in the japanese naavey, suggested that the disease was diet related.

1890 , Eijkman observed a beriberi-like condition (polyneuritis) in chicken.

1906, Jansen and 1926 (Funk) reported isolation of a material from rice polished which cured Beriberi. Jansen named the material aneuria. Vitamin B1, oryzamin, polyneuramin, vitamin F, antineuritic vitamin and antiberiberi vitamin.

In 1936 Thiamin was synthesized by Williams.

Lorestan University Structure of Thiamin, B1

• Named thiamin because it has both sulfur and amine group.

Lorestan University Source of Thiamin, B1

Sources of thiamin: Thiamin is widely distributed in the food supply even though some food had virtually no thiamin, polished rice, fats, oils, refined sugar, and unenriched flours are in this group.

Peas and other legumes seeds and soybean meal are good sources. the amount of thiamin increases with the maturity of the seed.

Whole-grain and cereal by products contain nutritionally significant amounts of thiamin.

Dried brewer’s yeast and wheat germ are both rich in thiamin.

Lorestan University Metabolism of B1

Dietary thiamin phosphates are hydrolyzed by intestinal phosphatases, and the resultant free thiamin is absorbed by active transport in the duodenum and proximal jejunum, with little absorption in the rest of the small intestine.

Thiamin active transport is sodium-independent and requires an outwardly directed proton gradient (i.e., it is dependent on a proton-pumping ATPase). Antimetabolites, such as pyrithiamin, compete with thiamin for active transport.

The transport system is saturated at relatively low concentrations of thiamin (about 2 µmol per L), thus limiting the amount of thiamin that can be absorbed.

Lorestan University Metabolism of B1

Both free thiamin and thiamin monophosphate circulate in plasma; about 60% of the total is the monophosphate.

Under normal conditions, most is bound to albumin; when the albumin binding capacity is saturated, the excess is rapidly filtered at the glomerulus and excreted in the urine.

Although a significant amount of newly absorbed thiamin is phosphorylated in the liver, all tissues can take up both thiamin and thiamin monophosphate, and are able to phosphorylate them to thiamin diphosphate and thiamin triphosphate.

Lorestan University Metabolism of B1

2-3% of the thiamin in nervous tissue is present as the triphosphate, which also occurs in significant amounts in skeletal muscle. In the nervous system, the triphosphate is found exclusively in the membrane fraction; muscle thiamin triphosphate is mainly cytosolic.

There are two pathways for formation of thiamin triphosphate from the diphosphate: 1. Phosphorylation by ATP, catalyzed by thiamin diphosphate kinase, which acts only on protein-bound thiamin diphosphate 2. Phosphorylation by ADP, catalyzed by adenylate kinase

Lorestan University Thiamin antagonist

There are two analogs of thiamin: 1-oxythiamin (an analog having the C-4 amino group replaced by a hydroxyl group) 2- pyrithiamin (a compound with the thiazole ring replaced by a pyridine).

Mechanisms of action: Oxythiamin is readily converted to the pyrophosphate and competes with thiamin for its place in the TPP-enzyme systems. Oxythiamin depresses appetite, growth, and weight gain and produces bradycardia, heart enlargement, and an increase in blood pyruvate, but it does not produce neurological symptoms. Pyrithiamin prevents the conversion of thiamin to TPP by interfering with the activity of thiamin kinase. Pyrithiamin results in a loss of thiamin from tissues, bradycardia, and heart enlargement, but does not produce an increase in blood pyruvate.

3-amprolin, Amprolium inhibits the absorption of thiamin from the intestine and blocks the phosphorylation of the vitamin.

Lorestan University Thiaminases a natural antagonist

A type of natural antagonist is a group of enzyme called thiaminases. The enzyme has several forms and has been found in fish, shellfish, ferns, betel nuts, and a variety of vegetables.

Antithiamin substances found in tea and other plant foods inactivate the vitamin. Tannic acid is one such substance; another is caffeic acid (3,4-dihydroxycinnamic acid). Some of the flavinoids and some of the dihydroxy derivatives of tyrosine have antithiamin activity.

Lorestan University Metabolic functions of Thiamin, B1

1- important coenzyme in several energy metabolism pathways. Thiamin is a part of the coenzyme thiamin pyrophosphate (TPP) (thiamin with two molecules of phosphate attached to it), also known as co-carboxylase, which is required in the metabolism of carbohydrates. Thiamin is also active in the decarboxylation of α-ketoglutaric acid to succinyl CoA in the citric acid cycle.

2- role in nerve and brain function (Combs,1992). In addition to its role as a coenzyme, it is speculated that thiamin has an independent role in neural tissue since it has been shown that stimulation of nerve fibers results in release of free thiamin and thiamin monophosphate. If a neurophysiologically active form of thiamin exists, it is as thiamin triphosphate.

Lorestan University Ruminants and Thiamin, B1

Amounts of thiamin synthesized daily in the rumen (28to72mg) have been reported to equal or exceed dietary intake (Brevesetal.,1981).

Thiamin is generally non toxic as the upper safe feeding level for most non ruminants is 1,000 times the requirement (NRC, 1987)

Lorestan University Deficiencies of Thiamin, B1

The biological half-life of thiamin is 10 to 20 days, and deficiency signs can develop rapidly during depletion.

1-when thiaminases associated with feeds (Bracken ferns and some raw fish products , Feeding diets high in sulphate) 2-thiaminase produced from altered ruminal fermentation (feeding diets rich in concentrate which cause a sudden drop in ruminal pH)

Deficiencies of thiamin block several of the energy producing Krebs cycle reactions. Deficiency of thiamin results in a central nervous system disorder.

Polioencephalomalacia (PEM), is the most common thiamin deficiency disorder. Symptoms of PEM include a profuse, but transient diarrhea, listlessness, circling movements, opisthotonus (head drawn back over neck), and muscle tremors. If treated promptly by parenteral injection of thiamin (2.2mg/kg of body weight), the condition can be reversed (NRC,1996).

Lorestan University • کمبود: دستگاه عصبی و قلب به خاط متابولیسم هوازی شان به کمبود آن حساسند. طیور: ستاره نگری stargrazing طیور بالغ بعد از سه هفته و جوجه ها بعد از 2 هفته عالئم کمبود را نشان می دهند. پاسخ به درمان خیلی سریع است)چند ساعت.(

نشخوارکنندگان: پلی انسفالوماالسیا )PEM

عالئم: اسهاال زیاد در مدت کوتاه، خستگی، حرکات دوار، ستاره نگری و تومورهای عضالنی علت: مصرف خوراک با کربوهیدرات محلول زیادکه منجر به رشد بیش از حد باکتریهای تولیدکننده تیامیناز میشود و جیره های حاوی سولفات زیاد

Lorestan University

Lorestan University Dietary recommendation of B1 • Monogasteric The thiamin needs of an individual are influenced by age, energy intake, carbohydrate intake, and body weight. 0.5 mg/1000 kcal (4184 kJ).

• Ruminants Amounts of thiamin synthesized daily in the rumen (28to72mg) have been reported to equal or exceed dietary intake (Brevesetal.,1981). High carbohydrated diet and high sulfur diet

Lorestan University

Riboflavin, B2

Lorestan University ریبو فالوین یک ماده زرد رنگ پرتغالی است .

منابع : مخمرها کبد کلیه منابع غنی از ریبوفالوین هستند. سبوس گندم، تخم مرغ، گوشت شیر و پنیرمنابع خوبی هستند. دانه غالت از لحاظ ریبوفالوین فقیرند. ریبوفالوین در برابر حرارت مقاوم است

کمبود: بیماری ریبوفالونوزیس در انسان

Lorestan University ساختمان ریبوفالوین در سال 1935 برای اولین بار سنتز شد. ریبوفالوین نسبت به نور و حرارت و اسید حساس است.

منابع: شیر، تخم مرغ، جگر جوانه غالت

Lorestan University ساختمان FAD , FMN

Lorestan University Riboflavin, B2

Riboflavin is a constituent of several enzyme systems associated with intermediary metabolism.

No dietary requirement for ruminants has been established. Tissue requirements are apparently met through microbial synthesis of the vitamin in the rumen as destruction of dietary riboflavin in the rumen is nearly 100 percent .

Milleretal.(1986) reported ruminal synthesis of riboflavin to be 148 percent of intake with apparent absorption from the small intestine averaging 23 percent.

Lorestan University Riboflavin, B2

• Exist in three forms • Free riboflavin • Coenzyme form • FMN (riboflavin 5-phosphate) • FAD

Lorestan University Riboflavin, B2

• Coenzyme derivatives are synthesized sequentially from riboflavin • • Riboflavin reacts with ATP to form FMN (Flavokinase • FMN combines with a second ATP to form FAD (FAD pyrophosphorylase)

• Loss • Milk pasteurization and exposure to the light (10-20%) • Bottled milk if standing in bright sunlight for more than 2 h (50- 70%)

Lorestan University Riboflavin, B2 • Metabolism • Free riboflavin covalently bound to protein is released by proteolysis • FAD and FMN (phosphorylated forms) • Hydrolyzed by phosphatases in the upper gastrointestinal tract (free vitamin for absorption) • Free vitamin enters mucosal cells of the small intestine after apparently being absorbed in all parts of small intestine

Lorestan University Riboflavin, B2 • Metabolism • At low concentrations + • Riboflavin absorption is an active Na - dependent carrier mediated process • At high concentrations • Ribofalvin is absorbed by passive transport

Lorestan University

Niacin, B3

Lorestan University Niacin

Niacin occurs in two forms (as an acid or as an amide). The vitamin is widely distributed in nature. Nicotinamide is the primary constituent of the coenzymes: NAD+ (nicotinamide adenine dinucleotide) NADP+ (nicotinamide dinucleotide phosphate)

Lorestan University Niacin

نیاسین یا نیکوتینیک اسید یا ویتامین B3 مشتقی اشت از پیریمیدین با یک گروه کربوکسیل در موقعیت کربن شماره 3 در نیکوتین آمید در موقعیت کربن شماره 3 یک کربوکسی آمید )CONH2( وجود دارد.

Niacin is a precursor to NADH, NAD+, NADP+ and NADPH, which play essential metabolic roles in living cells. Niacin is involved in both DNA repair, and the production of steroid hormones in the adrenal gland.

Lorestan University Riboflavin, B2 Niacin sources  Niacin is widely distributed in the human food supply. Especially good sources are whole grain cereals and breads, milk, eggs, meats, and vegetables that are richly colored.

 Unavailable Niacin in Cereals Chemical analysis reveals niacin in cereals (largely in the bran), is biologically unavailable, because it is bound as niacytin In wheat bran,60% is esterified to polysaccharides, and the remainder to polypeptides and glycopeptides . In calculation of niacin intakes, it is conventional to ignore the niacin content of cereals completely.

Lorestan University Niacin

 Niacin is widely distributed in the human food supply. Especially good sources are whole grain cereals and breads, milk, eggs, meats, and vegetables that are richly colored.

Lorestan University Niacin Absorption and metabolism Both nicotinic acid and nicotinamide cross the intestinal cell by way of simple diffusion and facilitated diffusion. After absorption the vitamin circulates in the blood in its free form, that is metabolized further and excreted in the urine. Niacin can be synthesized from tryptophan in a ratio of 60 molecules of tryptophan to 1 of nicotinic acid. Note the involvement of thiamin, vitamin B6, and riboflavin in this conversion.

Lorestan University Niacin

Lorestan University Niacin Niacin functions: • Carbohydrate metabolism

• Glycolysis • Krebs cycle • Lipid metabolism • Glycerol synthesis and breakdown • Fatty acid oxidation and synthesis • Steroid synthesis Niacin Niacin functions: • NAD

• Specific for hydrogenases involved in passing electrons on to oxygen, NAD participates as • Codehydrogenase with enzymes involved in oxidation of fuel molecluels •Glycerlyaldehyde 3-phosphate • Lactate •Alcohol •3-hydroxybutyrate • and a-ketoglutarate dehydrogenase Niacin Niacin functions: • Reduced NADP

• Synthesis of fats and steroids • Contained in alcohol -dehydrogenase system • Contained in lactate-dehydrogenase system • Hexose-mono phosphate shunt Niacin Niacin functions: • NAD and NADP

• Niacin-dependent poly(ADP-ribose) is involved in the post- translational modification of nuclear proteins •The poly ADP-ribosylated proteins seem to function as • in DNA repair, DNA replication, and cell differentiation Niacin

Niacin Niacin • In feeds is often present in a bound form that is not

available • Cereal grains and their by-products •Unavailable to simple-stomached animals • Much of it is also unavailable to rumen microorganisms • Two types of this unavailable form • Niacinogen • A carbohydrate complex Niacin

Niacin

Niacin requirments

Niacin Niacin • Requirements for ruminants

• Niacin Niacin deficiency • Severe metabolic disorders in the skin and digestive

tract • Loss of appetite •Retarded growth • Digestive disorders • Weakness •Diarrhea Niacin Niacin deficiency • Ruminants

• Young ruminants may suffer B-vitamins deficiency • Dietary requirements of niacin for young ruminants does not exist as long as the level of tryptophan is maintained near 0.2% of the diet • Sudden anorexia, severe diarrhea, inability to stand, dehydration followed by sudden death • Niacin supplementation may be beneficial to stressed animals (beef cattle being adapted to high-grain diets, lactating cows that have just calved) Niacin Niacin deficiency • Ruminants

• Beef cattle • Supplementation may improve average daily gain and feed efficiency (especially during adaptation period) (70 ppm added niacin) • Enhancing acclimation and adaptation to urea- supplemented diet • Supplemental niacin assist to overcome shipping stress and allows for a more rapid adjustment to feedlot conditions and changing the diets (50 or 100 ppm) Niacin Niacin deficiency • Ruminants

• Dairy cows • High producing dairy cows • 5 to 6 g /cow/day have a beneficial effect on milk production early in lactation period and when given to ketotic cows • 50 % of cows in a high producing herd go through borderline ketosis during the early lactation Niacin Niacin deficiency • Ruminants

• Dairy cows •50 % of cows in a high producing herd go through borderline ketosis during the early lactation • Supplementation with niacin (10 g/cow/day) reduced the concentration of serum beta hydroxybutyrate • Supplemental niacin • Increased miocrobial protein synthesis Niacin Niacin deficiency • Ruminants

• Dairy cows • Supplemental niacin • Increased miocrobial protein synthesis • 3-5 g supplementation resulted in slight increase in milk production in early lactation Niacin Niacin deficiency • Ruminants

• Lambs • 500 ppm supplementation improved feed efficiency of lambs fed a high concentrate diet containing urea • Increased performance in growing finishing lambs (100 ppm) Niacin Niacin deficiency • Ruminants

• Lambs • Supplemented niacin • Increased nitrogen utilisation • Improved the percentage of absorbed nitrogen retained • Reduced urinary nitrogen excretion • Reduced percentage of nitrogen found as urea nitrogen Niacin Niacin deficiency • Poultry

•Even chick and turkey embryos are able to synthesized niacin, but the rate of synthesis may be too slow for optimal growth • Broilers, 3-7 weeks of age are reported not to require supplemental niacin while fed a corn- soybean meal diet • 1-21 days of age vitamin is required Niacin Niacin deficiency • Poultry

• Enlargement of tibiotarsal joint • Bowing of the legs • Poor feathering • Dermatitis on the feet and head • The main clinical sign in young chicks is enlargement of hock joint, and bowing of the legs similar to perosis (Mn or choline deficiency) • In niacin deficiency the Achilles tendon rarely slips from its condyles

Niacin Niacin deficiency • Poultry

• Chick • Appetite loss • Blacktongue (inflammation of tongue and mouth cavity) beginning at two weeks of age • Mouth cavity and oesophagus becomes distinctly inflamed, growth is retarded and feed consumption is reduced

Niacin Niacin deficiency • Poultry

• Chick • Niacin Niacin deficiency • Poultry

• Turkey Poults , Pheasant chicks, ducklings and goslings • Perosis, primary niacin sign •Turkey poults, ducklings and pheasant chicks have a higher niacin requirements • Lower efficiency of conversion of tryptophan to niacin Pantothenic acid, B5

Pantothenic acid is a constituent of coenzyme A and is therefore essential for several fundamental reactions in metabolism including fatty acid oxidation, amino acid catabolism and acetyl choline synthesis. Sources: Meat, whole grain seed ( rice, wheat, alfalfa, molasses, yeasts) Pantothenic acid, B5

Pantothenic acid, B5

Pantothenic acid was isolated and synthesized in the late 1940s and recognized as an essential growth factor for yeast. Its essentiality for mammalian species did not become known until it was shown to prevent or cure chick dermatitis. It was subsequently recognized as essential for the rat, mouse, monkey, pig, dog, fox, turkey, fish, hamster and human. Pantothenic acid is synthesized by plant tissues but not by mammalian tissues. In 1946, it was discovered to be an essential part of coenzyme A.

Pantothenic acid, B5 Sources

Pantothenic acid is widely distributed in nature. Excellent food sources are organ meats, mushrooms, avocados, broccoli, and whole grains. Absorption occurs via facilitated diffusion and travels in the blood within the erythrocytes as well as in the plasma.

Pantothenic acid, B5 CHEMICAL STRUCTURE, PROPERTIES, AND ANTAGONISTS

•Pantothenic acid is an amide •Pantoic acid (α, γ-dihydroxy-β, β-dimethylbutyric acid) •β-alanine

Pantothenic acid, B5 CHEMICAL STRUCTURE, PROPERTIES, AND ANTAGONISTS

•Co-enzyme A

Pantothenic acid, B5 CHEMICAL STRUCTURE, PROPERTIES, AND ANTAGONISTS

•Analogs •Replaced β-alanine with other amino acids • α-alanine, β-aminobutyric acid, aspartic acid,leucine, or lysine, are inactive

Pantothenic acid, B5 CHEMICAL STRUCTURE, PROPERTIES, AND ANTAGONISTS •Antagonist •ω-methyl-panthothenic acid • pantoyltaurine, phenylpantothenate hydroxycobalamine (c-lactam) (analog of vitamin B12) • Feeding Chickens on high intake of copper • Reduced formation of acetyl-coA

• Increasing the oxidation of cysteine to cystine • Formation of copper-cysteine and copper-glutathione complexes Pantothenic acid, B5 CHEMICAL STRUCTURE, PROPERTIES, AND ANTAGONISTS •Antagonist •ω-methyl-panthothenic acid • pantoyltaurine, phenylpantothenate hydroxycobalamine (c-lactam) (analog of vitamin B12) • Feeding Chickens on high intake of copper • Reduced formation of acetyl-coA

• Increasing the oxidation of cysteine to cystine • Formation of copper-cysteine and copper-glutathione complexes Pantothenic acid, B5 Metabolism

•Found in both bound and free form • The bound co-enzyme form • Coenzyme A • Acyl carrier protein (ACP) • Prior to absorption • It is necessary to liberate the pantothenic acid from the bound forms in the digestive process • COA and other bound forms • hydrolyzed in the intestinal lumen to 4′- phosphopantetheine Pantothenic acid, B5 Metabolism

4′-phosphopantetheine

Dephosphorylated

Pantothenate

intestinal enzyme pantetheinase

Pantothenic acid Pantothenic acid, B5 Metabolism

• Pantothenic acid, its salt, and the alcohol are absorbed primarily in the jejunum by a specific transport system that is saturable and sodium ion dependent • After absorption •Pantothenic acid is transported to various tissues in the plasma, from which it is taken up by most cells via another active-transport process involving cotransport of pantothenate and sodium in a 1:1 ratio Pantothenic acid, B5 Metabolism

• Within all tissues • Pantothenic acid is converted to coenzyme A and other compounds in which the vitamin is a functional group • Animals and humans do not appear to have the ability to store appreciable amounts of pantothenic acid • Most pantothenic acid in blood exists in red blood cells as coenzyme A; serum contains no coenzyme A but does contain free pantothenic acid Pantothenic acid, B5 Functions

• Constituent of two important coenzymes—coenzyme A and ACP

Pantothenic acid, B5

Pantothenic acid, B5 Functions

• Acetyl-coA • Metabolism of carbohydrates, proteins, and lipids, and the synthesis of lipids, neurotransmitters, steroid hormones,porphyrins, and hemoglobin • Function of COA

•As a carrier mechanism for carboxylic acids • Such acids, when bound to coenzyme A, have a high potential for transfer to other groups and are normally then referred to as “active Pantothenic acid, B5 Functions

•Function of COA •Such acids, when bound to coenzyme A, have a high potential for transfer to other groups and are normally then referred to as “active •Most important of these reactions is the combination of coenzyme A with acetate to form “active acetate” (capable for further chemical reaction) • Combination with oxaloacetic acid to form citric acid

Pantothenic acid, B5 Functions

•Function of COA • Coenzyme A functions as a carrier of acyl groups in • Enzymatic reactions involved in synthesis of fatty acids, cholesterol, and sterols

In the oxidation of fatty acids, pyruvate, and α-ketoglutarate • • Biological acetylations Pantothenic acid, B5 Functions

•Function of COA • In the form of active acetate • Acetic acid can also combine with choline to form acetylcholine, the chemical transmitter at the nerve synapse, and can be used for detoxification of drugs including sulfonamides Pantothenic acid, B5 Functions

•ACP • Replaces coenzyme A during building of the carbon chain in synthesis of fatty acids •ACP is a protein with a sulfhydryl group covalently attached to acetyl, malonyl, and intermediate-chain acyl groups Pantothenic acid, B5 Functions

•Decarboxylation of ketoglutaric acid in the citric acid cycle yields succinic acid • Converted to the active form by linkage with coenzyme A • Active succinate

Active succinate and glycine are together involved • in thefirst step of heme biosynthesis Pantothenic acid, B5 Functions

•Pantothenic acid also stimulates synthesis of antibodies, which increase resistance of animals to pathogens • The 4′-phosphopantetheine is the prosthetic group of an enzyme system that synthesizes peptide antibodies, such as gramicidin in bacteria

Pantothenic acid, B5

Pantothenic acid, B5 Requirements

• If the rumen is functioning normally, ruminal microflora will synthesize enough pantothenic acid to satisfy ruminant needs • Vitamin synthesis is reduced with diets high in cellulose but increases with higher quantities of easily soluble Carbohydrates • Interrelationships with other vitamins (e.g., vitamin B12, vitamin C, and biotin) on pantothenic acid requirements are known 1982) Pantothenic acid, B5 Requirements

•Interrelationships with other vitamins (e.g., vitamin B12, vitamin C, and biotin) on pantothenic acid requirements are known

• Pantothenic acid requirement of chicks from B12-depleted hens was found to be greater than that of chicks from normal hens

• There is some evidence that pantothenic acid is involved in ascorbic acid synthesis in plants and animals Pantothenic acid, B5

Pantothenic acid, B5

•Pantothenic acid deficiency reduces normal egg production and hatchability

•Subcutaneous hemorrhage and severe edema in the developing chick embryo • decline of growth, followed by decline in feed conversion and retardation of feather growth

Pantothenic acid, B5

Calves

Vitamin B6 occurs in nature in three different forms which are interconvertible. It can be an aldehyde (pyridoxal), an alcohol (pyridoxine), or an amine (pyridoxamine).

Pyridoxine, pyridoxal, pyridoxamine, PLP, and pyridoxamine phosphate B6 Various forms of vitamin B6 can be destroyed by heat and alkali, and exposure to light,especially in neutral or alkaline media, is highly destructive

•The principal coenzyme form of vitamin B6 pyridoxal 5´phosphate (PLP; originally called codecarboxylase) B6

•Vitamin antagonists

• Either compete for reactive sites of apoenzymes or react with PLP to form inactive compounds • The majority of natural antagonists are substituted hydrazines and hydroxylamines • Substances that form hydrozones or oximes with pyridoxal or PLP • Antagonists frequently react with pyridoxal kinase, thus preventing the phosphorylated form of the vitamin B6

•Vitamin antagonists

•Deoxypyridoxine (not found in the nature) •Isonicotinic acid hydrazide (isoniazid), which is used in tuberculosis treatment • Strong inhibitor of pyridoxal kinase and results in anemia in humans • Inhibiting the synthesis of δ-aminolevulinic acid and thus of heme B6 •Vitamin antagonists •The antihypertensive drugs thiosemicarbizide and hydralazine interfere with B6 • Penicillamine, which is used to remove body copper in copper poisoning and Wilson’s disease

• Complex PLP • L-Dopa , an antiparkinsonism drug • Oral contraceptives (estrogen component)

•Presence of a vitamin B6antagonist in flax (linseed oil meal).

• Hydrazic acid and was found to have antibiotic properties B6 •Digestion, Absorption, and Transport •Digestion would first involve splitting the vitamin, as it is bound to proteins of foods

•B6 is absorbed mainly in the jejunum, but also in the ileum, by passive diffusion •Absorption from the colon is insignificant, even though colon microflora synthesize the vitamin

•Vitamin B6 compounds are mainly absorbed from the diet in the dephosphorylated forms, but phosphorylated forms can be absorbed to a very limited extent • The small intestine is rich in alkaline phosphatases forthe dephosphorylation reaction B6 •Digestion, Absorption, and Transport •Digestion would first involve splitting the vitamin, as it is bound to proteins of foods

•B6 is absorbed mainly in the jejunum, but also in the ileum, by passive diffusion •Absorption from the colon is insignificant, even though colon microflora synthesize the vitamin

• B6 compounds rapidly appear in liver, where they are mostly converted into PLP, considered to be the most active vitamin form in metabolism

Pyridoxine, pyridoxal, and pyridoxamine are widely distributed throughout the food supply. They are present in both plant and animal foods. Meats, cereals, legumes, nuts, fruits, and vegetables all contain the vitamin Its deficiency is rare, apart from an outbreak during the 1950s, which resulted from overheating of infant milk formula. A significant proportion (in some cases up to 75%) of the vitamin B6 in plant foods is present as glycosides. There may be some hydrolysis of glycosides in the gastrointestinal tract, and about half the vitamin present in foods as glycosides may be biologically available. However, pyridoxine glycosides are also absorbed intact (and excreted unchanged in the urine), and may compete for intestinal absorption and tissue uptake with the vitamin, thus having antivitamin activity.

B6 B6 functions: 1- metabolism of amino acids: 1-1- in transaminase reactions (and hence the inter conversion and catabolism of amino acids 1-2- in the synthesis of nonessential amino acids 1-3- in decarboxylation to yield biologically active amines 1-4- in a variety of elimination and replacement reactions. 2- cofactor for glycogen phosphorylase and a variety of other enzymes. 3- In addition, pyridoxal phosphate, the metabolically active vitamer, has a role in the modulation of steroid hormone action and the regulation of gene expression.

B6 B6 functions:

•Vitamin B6 acts as a component of many enzymes that are involved in the metabolism of proteins, fats, and carbohydrates • PLP (also named codecarboxylase), and to a lesser degree pyridoxamine phosphate, plays an essential role in the interaction of amino acid, carbohydrate, and fatty acid metabolism and the energy-producing citric acid cycle

B6 B6 functions:

•Pyridoxal phosphate functions • All reactions involved in amino acid metabolism • Transamination (aminotransferase), decarboxylation, deamination, and desulfhydration, and in the cleavage or synthesis of amino acids

B6 B6 functions: •The largest group of the vitamin B6-dependent enzymes are the transaminases • Most of which use α-ketoglutarates as the amino group acceptor

•Aminotransferases are involved in interconversions of a pair of amino acids into their corresponding keto acids

• these are α-amino and α-keto acids

• The aminotransferases thus represent an important link between amino acid, carbohydrate, and fatty acid metabolism and the energy- producing citric acid cycle B6

B6 B6 functions: • Nonoxidative decarboxylation reactions also involve PLP as a coenzyme •Decarboxylases convert amino acids to biogenic amines, such ashistamine, hydroxytyramine, serotonin, γ-

aminobutyric acid, ethanolamine,and taurine • Regulation of blood vessel diameter, neurohormonal actions, and essential components of phospholipids and bile acids B6

B6 Deficinecy: • Retarded growth, dermatitis, epileptic-like convulsions, anemia, and partial alopecia • Predominant function of the vitamin in protein metabolism •A fall in nitrogen retention is observed, feed protein is not well utilized, nitrogen excretion is excessive, and impaired tryptophan metabolism may result

B6 Deficinecy: • Ruminants • Adults no deficiency • stressed cattle, as a result of long-distance transportation, had very low blood pyridoxine concentrations

•Vitamin B6 has been shown to be essential for the young calf when selected experimental diets are used •Calves that were reared on a “milk substitute” lost appetite within 2 to 4 weeks; their growth was impaired; and they progressively showed apathy, diarrhea, loss of appetite, and loss of coordination B6 Deficinecy: • Poultry • Little appetite and grow slowly, with plumage failing to fully develop • General weakness after a few days of deprivation • Birds squat in a characteristic posture, with wings slightly spread and head resting on the ground

•High proportions of pendulous crops with vitamin B6-deficient chicks B6 Deficinecy:

B6 Deficinecy: • Poultry

• Specific sign of B6 deficiently is the nature of the nervous conditions that develop

Biotin, Vit H, B7

Biotin

Biotin was the name given to a substance isolated from egg yolk by Kögl and Tönnis in 1936 that was necessary for yeast growth. Other names given to this factor were protective factor X, egg-white injury protection factor, factor S, and factor W (or vitamin Bw).

Avidin: The glycoprotein avidin in egg white binds biotin with high affinity. Avidin is a protein that is a secretory product of the mucosa of the oviduct and therefore is found in the albuminous part of eggs. Biotin Structure of Biotin

Most biotin in foods is present as biocytin The chemical structure of biotin in metabolism includes a sulfur atom in its ring (like thiamin) and a transverse bond across the ring. Biotin is a fusion of an imidazolidone ring with a tetrahydrothiophene ring bearing a valeric acid side chain. Biotin Metabolism of Biotin Biotin exists in natural materials in both bound (biocytin ) and free forms. Biotinidase, present in pancreatic juice and intestinal mucosa, releases biotin from biocytin during the luminal phase of proteolysis. Biotin is absorbed by a sodium-dependent active transport process in the duodenum than the jejunum. Biotin appears to circulate in the bloodstream both free and bound to a serum glycoprotein, which also has biotinidase activity, catalyzing the hydrolysis of biocytin. All cells contain some biotin, with larger quantities in the liver and kidneys. Intracellular distribution of biotin corresponds to known localization of biotin-dependent enzymes (carboxylases). Biotin Sources of Biotin Biotin is present in many foods and feedstuffs. The

richest sources of biotin are royal jelly, liver, kidney, yeast, peanuts, and eggs. Most fresh vegetables and some fruits are fairly good sources.

Biotin

Biotin Function of Biotin Biotin is an essential coenzyme in carbohydrate, fat, and protein metabolism. It is involved in conversion of carbohydrate to protein and vice versa as well as conversion of protein and carbohydrate to fat. Maintaining normal blood glucose levels from metabolism of protein and fat when dietary intake of carbohydrate is low.

Biotin functions as a carboxyl carrier in four carboxylase enzymes: 1-pyruvate carboxylase, 2-acetyl CoA carboxylase, 3-propionyl CoA carboxylase, 4- 3-methylcrotonyl CoA carboxylase. Biotin Function of Biotin in carbohydrate metabolism Specific biotin-dependent reactions in carbohydrate metabolism are the following: 1-Carboxylation of pyruvic acid to oxaloacetic acid. 2-Conversion of malic acid to pyruvic acid. 3-Interconversion of succinic acid and propionic acid. 4-Conversion of oxalosuccinic acid to α-ketoglutaric acid.

Biotin Function of Biotin in protein and lipid metabolism In protein metabolism, biotin enzymes are important in protein synthesis, amino acid deamination, purine synthesis, and nucleic acid metabolism. Biotin is required for transcarboxylation in degradation of various amino acids. In lipid metabolism, Biotin is required for normal long -chain unsaturated fatty acid synthesis and is important for essential fatty acid metabolism. Acetyl- CoA carboxylase catalyzes addition of CO2 to acetyl- CoA to form malonyl-CoA. This is the first reaction in the synthesis of fatty acids which needs Biotin

Biotin

Biotin Effects of Biotin deficiency Biotin is important for normal function of the thyroid and adrenal glands, the reproductive tract, and the nervous system.

In Ruminants: a potassium-biotin interrelationship in calves, with the result that calves fed purified diets low in potassium and biotin developed progressive paralysis of the hind legs that spread to the forelegs, neck, and respiratory system. Death may result within 12 to 24 hours of the first signs; however, the condition can be cured by injections of potassium salts or biotin. preventing lameness in dairy cattle with biotin supplementation has been reported. Biotin

In poultry : The principal effects in both species are reduced growth rate and feed efficiency, disturbed and broken feathering, dermatitis, and leg and beak deformities

B12

Vitamin B12 is unique in that it is synthesized in nature only by microorganisms and in that the trace element cobalt is an integral part of the molecule. Cyanide, which lies above the planar ring, is attached to the cobalt atom—thus the name cyanocobalamin. The cyanide can be replaced by other groups, including OH (hydroxycobalamin), H2O (aquacobalamin), NO2 (nitrocobalamin), and CH3 (methylcobalamin). B12

Three seemingly unrelated conditions attributed to lack of the vitamin or its precursor were identified

(1) a fatal anemia in humans (2) A potent growth factor for monogastric species (3) a relationship to cobalt, the lack of which resulted in wasting diseases in ruminants

B12

•In 1964 another Nobel Prize was awarded to Hodgkin for her part in the elucidation of the chemical structure of vitamin B12 by x-ray crystallography •The significance of vitamin B12 for ruminants was discovered to be the requirement of cobalt by rumen microorganisms in order to synthesize the vitamin •The Australians showed that the cobalt deficiency caused debilitating diseases of sheep known as “coast disease” and “wasting disease.” • Cobalt deficiency responsible in part for “salt sick” cattle, describing a severe wasting disease B12

•The empirical formula of B12 is C63H88O14N14PCo • Unusual features is the content of 4.5% cobalt

B12

Structure of B12

B12

•Vitamin B12 resembles a porphyrin structure consisting of four pyrrole nuclei coupled directly to each other

• With the inner nitrogen atom of each pyrrole coordinated with a single atom of cobalt • The basic tetrapyrrole structure is the corrin nucleus Positionally is a planar structure coupled below to the nucleotide 5,6-dimethylbenzimidazole and above to cyanide or some other derivative B12

•The name “cobalamin” is used for compounds in which the cobalt atom is in the center of the corrin nucleus

•The cyanide can be replaced by other groups, including OH (hydroxycobalamin), H2O (aquacobalamin), NO2 (nitrocobalamin), and CH3 (methylcobalamin)

B12

Cyanocobalamine

B12

Hydroxycobalamine

B12

•Adenosylcobalamin, hydroxocobalamin, methylcobalamin, cyanocobalamin, and sulfitocobalamin have been determined in feedstuffs •The first three being the most predominant forms in animal tissue • The two coenzyme forms of cobalamin found in animals are adenosylcobalamin and methylcobalamin

•Cyanocobalamin, however, is the most widely used form of cobalamin in clinical practice because of its relative availability and stability (particularly to light) B12

•Oxidizing and reducing agents and exposure to sunlight tend to destroy its activity

•Losses of vitamin B12 during cooking are usually not excessive

B12

Digestion, Absorption, and Transport Vitamin B12 in the diet is bound to food proteins In the stomach, the combined effect of gastric acid and peptic digestion releases the vitamin, which is then bound to a nonintrinsic factor– cobalamin complex. The nonintrinsic protein that is secreted in the saliva has been named cobalophilin.

The B12 remains bound to cobalophilin in the slightly alkaline environment of intestine until pancreatic proteases (e.g., trypsin) partially degrade the cobalophilin protein and thereby enable B12 to become bound exclusively to intrinsic factor. Intrinsic factor is a glycoprotein (mucoprotein) synthesized and secreted by parietal cells of the gastric mucosa. The intrinsic factor–B12 complex is transiently attached to an ileal receptor. In portal blood B12 bounds to specific transport proteins called transcobalamins I, II, and III.

B12

Digestion, Absorption, and Transport •In the ileum, the intrinsic factor moiety of the intrinsic factor–B12 complex binds to a specific receptor protein on the microvillus membrane of brush borders of intestinal epithelial cells • Next there is transport of vitamin B12 from the receptor intrinsic factor– B12 complex through the epithelial cell to portal blood •When B12 enters the portal blood • When B12 enters the portal blood •Vit B12 binds to specific transport proteins called transcobalamins (I, II and III)

B12

•The transcobalamins are synthesized by several tissues, including intestinal mucosa and liver, and have been shown to deliver B12 to various tissues, such as liver, kidney, spleen, heart, lung, and small intestine • Transcobalamin II appears to be primarily concerned with transport of vitamin B12 •Transcobalamin I is involved in storage of the vitamin

•The function of transcobalamin III is to provide a

mechanism for returning vitamin B12 from peripheral tissues to the liver, as well as for clearance of other corrinoids

without vitamin activity (e.g., undesired analogs of B12) B12

•B12 absorption for most species studied requires

(1) adequate quantities of dietary B12

(2) normal stomach for breakdown of food proteins for

release of B12 (3) normal production of cobalophilin (nonintrinsic factor) secreted in saliva (4) normal stomach for production of intrinsic factor for absorption of B12 through the ileum (5) normal pancrease (trypsin) required for release of bound

B12 prior to combining the vitamin with the intrinsic factor B12

•B12 absorption for most species studied requires (6) Normal ileum with receptor and absorption sites

•Additional factors that diminish vitamin B12 absorption include deficiencies

• Protein, iron, and vitamin B6; thyroid removal; and dietary tannic acid

•Intrinsic factor has been demonstrated in the human, monkey,dog, pig, rat, cow, ferret, rabbit, hamster, fox, lion, tiger, and leopard

B12

•Intrinsic factor has been demonstrated in the human, monkey,dog, pig, rat, cow, ferret, rabbit, hamster, fox, lion, tiger, and leopard •It has not been detected in the guinea pig, horse, sheep, chicken, or a number of other species •Both active and passive mechanisms exist for absorption of B 12 •The passive mechanism, simple diffusion, has low efficiency (approximately 1%) and is operative throughout the digestive tract B12

•In ruminants • About 3% of ingested cobalt is converted to vitamin B12 in the rumen •Of the vitamin B12 produced, only 1 to 3% is absorbed •In the rumen, iron interacts with cobalt so that iron deficiency enhances cobalt absorption

B12

•Excretion • The main excretion of absorbed vitamin B12 is via urinary, biliary,and fecal routes

• Vitamin B12 is metabolically related to other essential nutrients, such as choline, methionine, and folacin

B12

•Functions • Specific biochemical reactions in which cobalamin coenzymes participate are of two types: •(1)those that contain 5´-deoxyadenosine linked covalently to the cobalt atom (adenosylcobalamin)

•(2) those that have a methyl group attached

to the central cobalt atom (methylcobalamin) B12

•Functions

• Only three vitamin B12-dependent enzymes have been discovered in animals: • Methylmalonyl CoA mutase and leucine mutase, which each require adenosylcobalamin •Methionine synthetase, which requires methylcobalamin

B12

B12 functions: (1) purine and pyrimidine synthesis (2) transfer of methyl groups (3) formation of proteins from amino acids (4) Carbohydrate and fat metabolism

A general function of B12 is to promote red blood cell synthesis and to maintain nervous system integrity, which are functions noticeably affected in the deficient state.

B12

Deficiency of B12

Deficiency of either folacin or B12 leads to impaired cell division and alterations of protein synthesis; these effects are most noticeable in rapidly growing tissues. Overall synthesis of protein is impaired in vitamin B12- deficient animals.

B12

Deficiency of B12 in ruminants In Ruminants, Young animals: poor appetite and growth, muscular weakness, demyelination of peripheral nerves, and poor general condition.

Sheep are more sensitive to cobalt deficiency than cattle. Acute clinical signs of cobalt deficiency include lack of appetite, rough hair coat, thickening of the skin, anemia (normocytic and normochromic), wasting away.

Cobalt deficiency has been reported to reduce lamb survival and increase susceptibility to parasitic infection in cattle and sheep. B12

Deficiency of B12 in poultry In growing chicks, turkey poults, and quail, vitamin B12 deficiency reduces body weight gain, feed intake, and feed conversion.

Additional clinical signs in B12 deficiency include anemia, gizzard erosion, and fattiness of heart, liver, and kidneys. Poor feathering and mortality are

the most obvious signs of vitamin B12 deficiency, and gizzard erosions may also appear.

In hens, body weight and egg production are maintained despite deficiency, but B12 has an important influence on egg size.

Hatchability of incubated eggs may be severely reduced if the

breeder diet contains inadequate vitamin B12.

B12

Folacin History •In the 1930s and early 1940s

•Active substances were described that were effective against nutritional deficiencies in humans, certain animals, and bacteria •Vitamin M, factor U, vitamin Bc, Bc conjugate, Lactobacillus casei factor, Streptococcus lactis R. (SLR) factor, folic acid,citrovorum factor, and others

Folacin Chemical structure •Folacin (pteroylglutamic acid) consist of

•Glutamic acid •ρ-aminobenzoic acid (PABA) •Pteridine nucleus

• The last two making up the petroic acid

Folacin Chemical structure

Folacin Chemical structure •In natural feedstuffs is conjugated with a varying number of

extra glutamic acid molecules

• Folacin as pteroyloligo--L-glutamates (PteGlun) is generally from one to nine glutamates long •Polyglutamate forms •Usually of 3 to 7 glutamyl residues linked by peptide bonds—of folacin are the natural coenzymes Folacin Chemical structure •The active forms of folacin contain

•A formyl group or a methyl group attached to the number 5 or number 10 nitrogens of the compound, or a methylene group between nitrogens 5 and 10 • Tetrahydrofolic acid is the principal coenzyme form, while the main storage form is 5-methyltetrahydrofolicacid

Folacin Chemical structure •Folate analogs

• Mainly for the purposes of anticancer (e.g., methotrexate and 5-fluorouracil) and antitumoral therapy •Folacin deficiency is more detrimental to cells that are rapidly growing

Folacin Chemical structure •Folate analogs can act by

• Blocking conversion of pteroylmonoglutamic acid to tetrahydrofolic acid by binding to dihydrofolic acid reductase • Blocking the transfer of single-carbon units from tetrahydrofolic acid to acceptors, such as in synthesis of methionine or purines Folacin Chemical structure •Sulfonamides

•Are analogs of the folacin biosynthetic intermediate PABA and are widely used as antibacterial agents

Folacin Metabolism •Polyglutamate forms are digested

• Hydrolysis to pteroylmonoglutamate prior to transport across the intestinal mucosa • Hydrolysis is catalyzed by a conjugase intestinal enzyme found in the brush border •γ-carboxy peptidase (a pH optimum near neutrality and is activated by zinc) •In humans, a zinc deficiency resulted in a decreased intestinal hydrolysis of pteroylpolyglutamate Folacin Metabolism •Conjugase activity • Is reduced by nutritional zinc deficiency, chronic consumption of alcohol, and exposure to naturally occurring inhibitors in foods • Absorption

•Pteroylmonoglutamate is absorbed predominantly in the jejunum, with lesser amounts in the duodenum •Na+-coupled carrier-mediated process •Folacin is also absorbed passively (accounts for 20 to 30% of folacin absorption) Folacin Metabolism •Conjugase activity • Is reduced by nutritional zinc deficiency, chronic consumption of alcohol, and exposure to naturally occurring inhibitors in foods • Absorption

•Pteroylmonoglutamate is absorbed predominantly in the jejunum, with lesser amounts in the duodenum •Na+-coupled carrier-mediated process •Folacin is also absorbed passively (accounts for 20 to 30% of folacin absorption) Folacin Metabolism •Transportation • Are transported in plasma as monoglutamate derivativeswith only limited methylation (5- methyltetrahydrofolate) • In the liver

• Is converted primarily to 5-methyltetrahydrofolate and 10-formyltetrahydrofolate and then transported to the peripheral tissues Folacin Metabolism •Transportation • Monoglutamate derivatives • are then taken up by cells in tissues by specific transport systems •The pteroylpolyglutamates—the major folacin form in cells—are built up again in stepwise fashion by the enzyme folate polyglutamate synthetase •Polyglutamation traps folates inside cells at concentrations one to two orders of magnitude greater than those of extracellular fluids Folacin Metabolism •Transportation • Folacin enzymes are compartmentalized between the cytosol and the mitochondria • Specific folate-binding proteins (FBPs) • Bind folacin monoglutamates and polyglutamates • Liver, kidney, small intestinal brush border membranes,leukemic granulocytes, blood serum, allantoic fluid, and milk Folacin Metabolism •Transportation • Specific folate-binding proteins (FBPs) • They play a role in folacin transport analogous to

the intrinsic factor in the absorption of vitamin B12 •The FBPs may play a role in tissue storage of folacin

•By protecting the polyglutamate derivatives from the action of degradative or hydrolytic enzymes Folacin Storage •Folacin is widely distributed in tissues largely in the conjugated polyglutamate forms •Vitamin B12 deficiency •Defects in the conversion of pteroylmonoglutamates to polyglutamate forms that lead to a decreased tissue ability to retain intracellular folacin

Folacin Functions •In the form 5,6,7,8-tetrahydrofolic acid, is indispensable in transfer of single-carbon units in various reactions •Biosynthesis of: •lipids, • proteins, • nucleic acid derivatives, • hormones,and neurotransmitters—a role analogous to that of pantothenic acid in the transfer of two-carbon units Folacin Functions •pathway providing methyl groups in the transfer of two- carbon units •Involves transfer of a one-carbon unit from serine to tetrahydrofolate to form 5,10-methylenetetrahydrofolate •5,10-methylenetetrahydrofolate is subsequently reduced to 5-methyltetrahydrofolate • Methyltetrahydrofolate:

• Supplies methyl groups to remethylate homocysteine in the activated methyl cycle, providing methionine for synthesis of the important methyl donor agent S- adenosylmethionine Folacin Functions

Folacin metabolism requiring one-carbon units Folacin Functions •These one-carbon units are generated during • Amino acid metabolism

• Are used •In the metabolic interconversions of amino acids and in the biosynthesis of the purine and pyrimidine •Components of nucleic acids •Needed for cell division Folacin Functions •Specific reactions involving single-carbon transfer by folacin •Purine and pyrimidine synthesis •Interconversion of serine and glycine

• Glycine-α-carbon as a source of C1 units for many syntheses

•Histidine degradation •Synthesis of methyl groups for such compounds as methionine, choline, and thymine Folacin Functions •Folacin deficiency • Reduction in the biosynthesis of nucleic acids essential for cell formation and function •Impaired cell division and alterations of protein synthesis (rapidly growing tissues)

•Absence of adequate nucleoproteins

• Normal maturation of primordial red blood cells does not take place Folacin Functions •Folacin deficiency •Normal maturation of primordial red blood cells does not take place •Hematopoiesis is inhibited at the megaloblast stage

•peripheral blood picture results that is characterized by macrocytic anemia

•White blood cell formation is also affected •Thrombopenia, leukopenia, and old, multilobed neutrophils Folacin Functions

•Vitamin B12 is also closely associated with the progress of the folacin-dependent reactions of intermediary metabolism • Vitamin B12 regulates the proportion of methyl to non-methyltetrahydrofolates according to the methyl trap theory

•Vitamin B12 is necessary for transport of methyl-THF across the cell membrane and promotes folacin retention by tissues Folacin

Folacin Sources •Folacin is widely distributed in nature, almost exclusively as THF acid derivatives

Folacin Sources

Folacin DEFICIENCY •Macrocytic anemia (megaloblastic anemia) and leukopenia (reduced number of white cells) •Ruminants •Young animals that do not have a fully developed rumen would be expected to be folacin deficient •Folacin deficiency in lambs fed synthetic diets •Leukopenia followed by diarrhea, pneumonia, and death Folacin DEFICIENCY •Poultry

•Retarded growth and feed efficiency •Severe macrocytic anemia •In chicks is also characterized by poor growth, very poor feathering, anemic appearance, and perosis •Chicks become lethargic and feed intake declines. As anemia develops, the comb becomes waxy white, and mucous membrane of themouth becomes pale Vitamin C

Vitamin C is a vitamin for only a limited number of vertebrate

species: humans and the other primates, the guinea pig, bats, birds, and most fishes. Vitamin C primarily occurs in two forms:

1- reduced ascorbic acid

2- oxidized dehydroascorbic acid

Vitamin C

•The sole function of vitamin C is to prevent scurvy!!!

•Larger quantities may be required to maintain good health during conditions of adverse environment, physiological stress, and certain diseases

•Play important role in animal and human health by inactivating harmful free radicals produced through normal cellular activity and from various stressors Vitamin C

CHEMICAL STRUCTURE, PROPERTIES, AND ANTAGONISTS

•Occurs in two forms •The reduced ascorbic acid •The oxidized dehydroascorbic acid • Both form are biologically active Vitamin C

Vitamin C

CHEMICAL STRUCTURE, PROPERTIES, AND ANTAGONISTS

•Vitamin C may reversibly oxidize to the dehydro form •Dehydroascorbic acid further oxidized to the inactive and irreversible compound of diketogulonic acid •Vitamin C is very susceptible to destruction through oxidation, a change that is accelerated by heat and light •Diketogulonic acid can be further oxidized to oxalic acid and L-threonic acid Vitamin C

CHEMICAL STRUCTURE, PROPERTIES, AND ANTAGONISTS

•There are four stereoisomers of ascorbic acid; in addition to the L-isomer

•Only erythorbic acid (D-araborascorbic acid) has activity •Used in the food industry for addition to meats or canning operations as an antioxidant Vitamin C

CHEMICAL STRUCTURE, PROPERTIES, AND ANTAGONISTS

•A number of chemical substances are antagonistic to vitamin C

•Air pollutants, industrial toxins, heavy metals, tobacco smoke, and several pharmacologically active compounds, among them some antidepressants and diuretics Vitamin C

METABOLISM

•Vitamin C is absorbed in a manner similar to that of carbohydrates (monosaccharides) •Intestinal absorption in vitamin C-dependent animals appears to require a Na+-dependent active transport system

•Those species that are not prone to scurvy have an absorption mechanism by diffusion Vitamin C

METABOLISM

•The site of absorption •In the guinea pig is in the duodenal and proximal small intestine •In the rat, the highest absorption is in the ileum •In humans: •Predominantly in the distal portion of the small intestine and, to a lesser extent, in the mouth, stomach, and proximal intestine Vitamin C

METABOLISM

•In its metabolism •Ascorbic acid is first converted to dehydroascorbate by a number of enzyme or nonenzymatic processesand is then reduced in cells •Transportation • Vitamin C is transported in the plasma in association with the protein albumin Vitamin C

METABOLISM

•Ascorbic acid is widely distributed throughout the tissues •Highest concentrations of vitamin C are found in •The pituitary and adrenal glands, with high levels also found in the liver, spleen, brain, and pancreas •The vitamin tends to localize around healing wounds •Tissue levels are decreased by virtually all forms of stress, which also stimulates the biosynthesis of the vitamin in those animals capable of synthesis Vitamin C

METABOLISM

•Excretion •In urine, sweat, and feces

Vitamin C

FUNCTIONS

•Involved in a number of biochemical processes that involve donation of one or two electrons •Function of vitamin C is related to •Its reversible oxidation and reduction characteristics •Vitamin C plays important roles in many biochemical reactions • Mixed-function oxidation involving incorporation of oxygen into the substrate Vitamin C

FUNCTIONS

•Collagen Synthesis •Collagens are the tough, fibrous, intercellular materials (proteins) that are principal components of skin and connective tissue, the organic substances of bones and teeth

•Impairment of collagen synthesis in vitamin C deficiency appears to be due to lowered ability to hydroxylate lysine and proline Vitamin C

FUNCTIONS

•Collagen Synthesis •Syntheses of collagens involve •Enzymatic hydroxylations of

•Proline to form a stable extracellular matrix

•Lysine for glycosylation and formation of cross-links in the fibers Vitamin C

FUNCTIONS

•Collagen Synthesis •Hydroxyproline residues contribute to the stiffness of the collagen triple helix • Hydroxylysine residues bind (via their hydroxyl groups) carbohydrates and form intramolecular cross-links that give collagen structural integrity Vitamin C

FUNCTIONS

•Vitamin C is required for differentiation of mesenchyme (embryonic cells capable of developing into connective tissue) tissue)-derived connective tissues •Muscle, cartilage, and bone •Hydroxyproline is found only in collagen (14%) and arises from hydroxylation of proline •In its absence, a nonfibrous collagen precursor is formed instead of fibrous collagen and would result in scurvy Vitamin C FUNCTIONS •Antioxidant and Immunity Role

•Free radicals can be extremely damaging to biological systems • Hydroxy, hypochorite, peroxy, alkoxy, superoxide, hydrogen peroxide, and singlet oxygen •Are generated by auto-oxidation, radiation, or from activities of some oxidases, dehydrogenases, and peroxidases •Also, phagocytic granuylocytes undergo respiratory burst to produce oxygen radicals to destroy the intracellular pathogens Vitamin C FUNCTIONS •Antioxidant and Immunity Role

•Antioxidants serve to stabilize these highly reactive free radicals, thereby maintaining the structural and functional integrity of cells

•Antioxidants are very important to immune defense and health of humans and animals Vitamin C FUNCTIONS •Antioxidant and Immunity Role

•Tissue defense mechanisms against free-radical damage generally include • Vitamin C, vitamin E, and β-carotene as the major vitamin an tioxidant sources

Vitamin C FUNCTIONS •Antioxidant and Immunity Role

•Several metalloenzymes •Glutathioneperoxidase (selenium), catalase (iron), and superoxide dismutase (copper, zinc, and manganese), are also critical in protecting the internal cellular constituents from oxidative damage Vitamin C FUNCTIONS •Antioxidant and Immunity Role

•The antioxidant function of these vitamins could, at least in part, enhance immunity by maintaining the functional and structural integrity of important immune cells

• Vitamin C is the most important antioxidant in extracellular fluids • Vitamin C can protect biomembranes against lipid peroxidation damage by eliminating peroxyl radicals in the aqueous phase before the latter can initiate peroxidation Vitamin C FUNCTIONS •Antioxidant and Immunity Role

•Ascorbic acid have a stimulating effect on •Phagocytic activity of leukocytes, on function of the reticuloendothelial system, and on formation of antibodies

•Vitamin C can stimulate the production of interferons, the proteins that protect cells against viral attack Vitamin C FUNCTIONS •Antioxidant and Immunity Role

•One of the protective effects of vitamin C may partly be mediated through its ability to reduce circulating glucocorticoids

•The suppressive effect of corticoids on neutrophil function in cattle is alleviated with vitamin C supplementation Vitamin C FUNCTIONS •Antioxidant and Immunity Role

•Ascorbate can regenerate the reduced form of α- tocopherol,perhaps accounting for observed sparing effects of these vitamins

•In the process of sparing fatty acid oxidation, tocopherol is oxidized to the tocopheryl free radical. Ascorbic acid can donate an electron to the tocopheryl free radical, regenerating the reduced antioxidant form of tocopherol Vitamin C REQUIREMENTS

Wide variety of plant and animal species can synthesize vitamin C from carbohydrate precursors, including glucose and galactose.

Vitamin C

Vitamin C Deficiency Ruminants and poultry are able to synthesize vitamin C, and

thus it is assumed they do not require dietary sources of the vitamin.

Humans: In humans, gross vitamin C deficiency results in scurvy, a disease characterized by multiple hemorrhages

Vitamin A

Vitamin A •Vitamin A may be considered the most important vitamin from a practical standpoint • It is important as a dietary supplement for all animals, including ruminants •Vitamin A itself does not occur in plants

•Its precursors (carotenoids) are found in plants, and these can be converted to true vitamin A by a specific enzyme located in the intestinal walls of animals Vitamin A •Vitamin A may be considered the most important vitamin from a practical standpoint • It is important as a dietary supplement for all animals, including ruminants •Vitamin A itself does not occur in plants

•Its precursors (carotenoids) are found in plants, and these can be converted to true vitamin A by a specific enzyme located in the intestinal walls of animals Vitamin A •Farmers complained that hogs in dry lot or barns did poorly when fed a ration consisting largely of white corn instead of yellow corn •Agricultural chemists would disagree •White corn has no carotene, the precursor of vitamin A • In human nutrition, vitamin A is one of the few vitamins of which both deficiency and excess constitute a serious health hazard Vitamin A •Deficiency is considered to be the most common cause of blindness in young children throughout the world •Vitamin A toxicity usually arises from abuse of vitamin supplementation

Vitamin A •CHEMICAL STRUCTURE AND PROPERTIES Vitamin A itself does not occur in plant products, but its precursor, carotene occurs in several forms

Vitamin A

Vitamin A •CHEMICAL STRUCTURE AND PROPERTIES •Vitamin A itself does not occur in plant products, but its precursor, carotene occurs in several forms • These compounds are commonly referred to as provitamin A because the body can transform them into the active vitamin •The combined potency of a feed, represented by its vitamin A and carotene content, is referred to as its vitamin A value Vitamin A •CHEMICAL STRUCTURE AND PROPERTIES •Retinol is the alcohol form of vitamin A •Replacement of the alcohol group by an aldehyde group gives retinal •Replacement by an acid group gives retinoic acid

•Esters of retinol are called retinyl esters

•Vitamin A in animal products exists in several forms, but principally as long-chain fatty acid esters (e.g., retinyl palmitate) Vitamin A •CHEMICAL STRUCTURE AND PROPERTIES •In addition to retinol, there is another form that is isolated from fish

•Named A2 to differentiate it from the previously isolated form

•Vitamin A2 is closely related to vitamin A1 but contains an additional double bond in the β-ionone ring •The relative biological activity of vitamin A2 is 40 to 50% that of A1 Vitamin A •CHEMICAL STRUCTURE AND PROPERTIES •The vitamin is made up of isoprene units with alternate double bonds, starting with one in the β-ionone ring that is in conjugation with those in the side chain • Double bonds • Vitamin A can exist in different isomeric forms

Vitamin A

Vitamin A •CHEMICAL STRUCTURE AND PROPERTIES •The most active vitamin A form and that most usually found in mammalian tissues is the all-trans-vitamin A •cis-Forms can arise from the all-trans-forms, and a marked loss of vitamin A potency results • Structural changes in the molecule are promoted by moisture,heat, light, and catalysts •Conditions present during hay making and ensiling, dehydrating, and storage of crops are detrimental to the biological activity of any carotenoids present Vitamin A •CHEMICAL STRUCTURE AND PROPERTIES •Precursors of vitamin A • Carotenes •500 carotenoids that have been isolated from nature • Only 50 to 60 possess biological activity •α-carotene, β−carotene, γ-carotene, and cryptoxanthine (the main carotenoid of corn) are of particular importance because of their provitamin A activity Vitamin A •CHEMICAL STRUCTURE AND PROPERTIES •Precursors of vitamin A • Vitamin A activity of β−carotene is substantially greater than that of other carotenoids • Lycopene is an important carotenoid for its antioxidant Function •Does not possess the β−ionone ring structure, and therefore is not a precursor of vitamin A Vitamin A •CHEMICAL STRUCTURE AND PROPERTIES •Precursors of vitamin A • Theoretically, 1 mol of β−carotene could be converted •Only one molecule of vitaminA is formed from one molecule of β−carotene

• Loss of potential activity results from inefficient cleavage and intestinal absorption

Vitamin A •CHEMICAL STRUCTURE AND PROPERTIES •Vitamin A activity •Is expressed in international units •An IU is defined as the biological activity of 0.300 μg of vitamin A alcohol (retinol) or 0.550 μg of vitamin A palmitate •One IU of provitamin A activity is equal in activity to 0.6 μg of β−carotene Vitamin A •METABOLISM •Digestion •Vitamin A in animal products and carotenoids •Are released from proteins by the action of pepsin in the stomach and proteolytic enzymes in the small intestine •In the duodenum •Bile salts break up fatty globules of carotenoids and retinyl esters to smaller lipid congregates, which can be more easily digested by pancreatic lipase, retinyl ester hydrolase, and cholesteryl ester hydrolase Vitamin A •METABOLISM •Absorption and Transport •Conversion of β−carotene to vitamin A takes place in the intestinal mucosa •Conversion of β−carotene into vitamin A involves two enzymes •β−Carotene-15,15´-dioxygenase •Catalyzes the cleavage of β−carotene at the central double bond to yield two molecules of retinal for one molecule of β−carotene Vitamin A •METABOLISM •Absorption and Transport •β−Carotene-15,15´-dioxygenase •Random (eccentric) cleavage • Resulting in retinoic acid and retinal, with a preponderance of apocarotenals formed as intermediates •The cleavage enzyme has been found in many vertebrates but is not present in the cat or mink Vitamin A •METABOLISM •Absorption and Transport •The second enzyme •Retinaldehyde reductase • Reduces the retinal to retinol

•In most mammals •The product ultimately absorbed from the intestinal tract as a result of feeding carotenoids is mainly vitamin A itself Vitamin A •METABOLISM •Absorption and Transport •Species specificity regarding the ability to absorb dietary carotenoids • Rat, pig, goat, sheep, rabbit, buffalo, and dog, almost all of the carotene is cleaved in the intestine •In humans, cattle, horses, and carp, significant amounts of carotene can be absorbed •Absorbed carotene can be stored in the liver and fatty tissues •These latter animals have yellow body and milk fat Vitamin A •METABOLISM •Absorption and Transport •In the case of cattle

• Strong breed difference in absorption of carotene • The Holstein is an efficient converter, having white adipose tissue and milk fat

•The Guernsey and Jersey breeds, however, readily absorb carotene, resulting in yellow fat Vitamin A •METABOLISM •Absorption and Transport •The chick •Absorbs only hydroxy carotenoids in the unchanged form and stores them in tissues

•Hydrocarbon carotenoids with provitamin A activity are converted by the chick intestine and absorbed as vitamin A Vitamin A •METABOLISM •Absorption and Transport •Factors affect absorption of carotenoids •cis-trans-isomerism of the carotenoids is important in determining their absorbability

•trans-forms being more efficiently absorbed

• Dietary fat is important •Dietary antioxidants (e.g., vitamin E) •It is uncertain whether the antioxidants contribute directly to efficient absorption or whether they protect both carotene and vitamin A from oxidative breakdown Vitamin A •METABOLISM •Absorption and Transport •The main site of vitamin A and carotenoid absorption is the mucosa of the proximal jejunum •The absorption of vitamin A in the intestine is believed to be 80 to 90%, while that of β−carotene is about 50 to 60% •Carotenoids are normally converted to retinol in the intestinal mucosa but may also be converted in the liver and other organs, especially in yellow fat species such as poultry Vitamin A •METABOLISM •Absorption and Transport •Lipid micelles in the intestinal lumen serve as carriers •By taking up vitamin A and carotene from emulsified dietary lipid and bringing these lipids into contact with the mucosal cell •They diffuse from the micelle through the lipid portion of the microvillar membrane Vitamin A •METABOLISM •Absorption and Transport •Vitamin A occurs in food primarily as the palmitate ester •Hydrolyzed in the small intestine by retinyl ester hydrolase

•Secreted by the pancreas

•Bile salts are required both for the activation of this enzyme and for the formation of the lipid micelle, which carries vitamin A from the emulsified dietary lipid to the microvillus Vitamin A •METABOLISM •Absorption and Transport •Vitamin A is absorbed almost exclusively as the free alcohol, retinol • Within the mucosal cells, retinol is reesterified mostly to palmitate •Is incorporated into the chylomicra of the mucosa, and is secreted into the lymph •A small amount of retinol may be oxidized first to retinal and then to retinoic acid, which may form a glucuronide and pass into the portal blood Vitamin A •METABOLISM •Absorption and Transport •A specific transporter in the intestinal brush border for alltrans - and 3-dehydroretinol •Constituting a process of carrier-facilitated diffusion

•Other retinoids studied were taken up by passive diffusion at a slower rate

Vitamin A •METABOLISM •Absorption and Transport •Vitamin A is transported through the lymphatic system •With a low density lipoprotein in lymph acting as a carrier to the liver, where it is deposited mainly in hepatocytes and stellate and parenchymal cells • When vitamin A is mobilized from the liver •Stored vitamin A ester is hydrolyzed (retinyl ester hydrolase) prior to its release into the bloodstream, and vitamin A alcohol (retinol) then travels via the blood stream to the tissues Vitamin A •METABOLISM •Absorption and Transport •Retinol is transported by a specific transport and binding protein, retinol-binding protein (RBP) •The RBP is synthesized and secreted by hepatic parenchymal cells

Vitamin A •METABOLISM •Absorption and Transport •Retinol is secreted from liver in association with RBP and circulates to peripheral tissues complexed to a • Thyroxine-binding protein, transthyretin

•The retinoltransthyretin complex is transported to target tissues •Binds to a cell-surface receptor and the retinol is transported into cells of target tissue Vitamin A •METABOLISM •Absorption and Transport •Once the retinoids are transferred into the cell • They are quickly bound by specific binding proteins in the cell cytosol

• The intracellular retinoid-binding proteins bind retinol, retinal, and retinoic acid for purposes: •Protection against decomposition, solubilize them in aqueous medium, render them nontoxic, and transport them within cells to their site of action Vitamin A •METABOLISM •Absorption and Transport •These binding proteins also function by presenting the retinoids to the appropriate enzymes for metabolism

Vitamin A

Vitamin A •METABOLISM •Absorption and Transport •Some of the principal forms of intracellular (cytoplasmic ) retinoid-binding proteins •Cellular retinol-binding proteins (CRBP I and II)

•Cellular retinoic acid-binding proteins (CRABP I and II)

•Cellular retinaldehyde binding protein (CRALBP) •Six nuclear retinoic acid receptors (RAR α, β, γ and RXR α, β, γ) Vitamin A •METABOLISM •Absorption and Transport •The cellular retinol and retinoic acid-binding proteins— CRBP (I, II) and CRABP (I, II) •Function in transport and metabolism of retinoids within parenchymal, intestinal, reproductive, and fetal cells and across blood-organ barriers •A different group of retinoid-binding proteins •Related to serum retinol-binding protein, functions in epididymis and uterus Vitamin A •METABOLISM •Absorption and Transport •Retinaldehyde-binding protein aids •In the oxidation-reduction reaction of 11-cis-retinol–11- cis-retinaldehyde in the retina

•Where the interphotoreceptor retinol-binding protein transports retinol between pigment epithelium and photoreceptors

Vitamin A •METABOLISM •Absorption and Transport •There are two classes of nuclear receptors •All-trans-retinoic acid is the ligand for RAR •9-cis-retinoic acid is the ligand for RXR

• Receptors for 1,25-dihydroxyvitamin D3, all-trans retinoic acid, and 9-cis-retinoic acid are members of the nuclear hormone receptor super family

Vitamin A •METABOLISM •Absorption and Transport

•Receptors for 1,25-dihydroxyvitamin D3, all-trans retinoic acid, and 9-cis-retinoic acid are members of the nuclear hormone receptor super family •Having at least 30 members, including receptors for the classic steroid hormones (estrogen, progesterone, glucocorticoids, androgens, thyroid hormone, and several others) •They control gene expression by interacting with specific DNA sequences or regulatory elements in control regions of target genes Vitamin A •METABOLISM •Storage •Liver normally contains about 90% of total-body vitamin A •The remainder is stored in the kidneys, lungs, adrenals, and blood, with small amounts also found in other organs and tissues

Vitamin A •FUNCTIONS •Vitamin A is necessary for •Support of growth, health, and life of higher animals •Vitamin A deficiency causes at least four different and probably physiologically distinct lesions

•Loss of vision due to a failure of rhodopsin formation in the retina

•Defects in bone growth •Defects in reproduction (e.g., failure of spermatogenesis in the male and resorption of the fetus in the female) •Defects in growth and differentiation of epithelial tissues, frequently resulting in keratinization Vitamin A •FUNCTIONS •Defects in growth and differentiation of epithelial tissues, frequently resulting in keratinization • Keratinization of these tissues •Loss of function; this occurs in the alimentary, genital, reproductive, respiratory and urinary tract • Make the affected tissue more susceptible to infections •Thus, diarrhea and pneumonia are typical secondary effects of vitamin A deficiency Vitamin A •FUNCTIONS •Retinoic acid •Has been shown to perform as a hormone (e.g., all- trans-retinoic acid and 9-cis-retinoic acid) •Support growth and tissue differentiation but not vision or reproduction •Retinol is needed for normal vision and some aspects of reproduction •Most, if not all, actions of vitamin A in development, differentiation, and metabolism are mediated by nuclear receptor proteins that bind retinoic acid, the active form of vitamin A Vitamin A •FUNCTIONS •Retinoic acid •A group of retinoic acid binding proteins (receptors) function in the nucleus by •Attaching to promoter regions in a number of specific genes •Stimulate their transcription and thus affect growth, development, and differentiation Vitamin A •FUNCTIONS •Six high-affinity receptor proteins for retinoic acid (RAR α, β, γ and RXR α, β, γ) have been identified

•RAR nuclear receptors bind to all-trans retinoic acid, while RXR receptors bind with 9-cis-retinoic acid •Retinoic acid receptors in cell nuclei •Structurally homologous and functionally analogous to the known receptors for steroid hormones, thyroid

hormone(triiodothyronine),and vitamin D [1,25-(OH)2D] Vitamin A •FUNCTIONS •Retinoic acid •Function as a hormone to regulate the transcription activity of a large number of genes •Example:

• Connection between vitamin A deficiency and hepatic glycogen depletion caused by reduced gluconeogenesis •Can be explained at the molecular level by the dependence of phosphoenolpyruvate carboxykinase gene expression on adequate vitamin A Vitamin A •FUNCTIONS •Actions of vitamin A in development, differentiation, and metabolism

• Mediated by nuclear receptor proteins (RARs and RXRs) that bind retinoic acid with steroid and thyroid hormone receptors •The super family of nuclear proteins interact with specific genes and regulate their transcription • Retinoic acid has been found to stimulate, synergistically with thyroid hormone •The production of growth hormone in cultured pituitary cells Vitamin A •FUNCTIONS •Retinoic acid plays an important role in growth and differentiation of embryonic tissues

•Regulates the differentiation of epithelial, connective, and hematopoietic tissues

Vitamin A •FUNCTIONS •Vision •Vitamin A is an essential component of vision •Retinol is utilized in the aldehyde form (transform to 11-cis-retinal) in the retina of the eyes:

•The prosthetic group in rhodopsin for dim light vision (rods) •The prosthetic group in iodopsin for bright light and color vision (cones) Vitamin A •FUNCTIONS •Vision •11-cis-retinal (aldehyde form of vitamin A) is combined with the protein opsin, rhodopsin (visual purple) is produced •Rhodopsin breaks down in the physiological process of sight as a result of photochemical reaction Be stored as 11-cis retinlyl esters or Pigment epithelium: Plasma RBP Transported to the photoreceptor rods and cones of the retina cells bound to an interreceptor retinoid binding protein

Vitamin A •FUNCTIONS •Vision •Photoexcited rhodopsin activates transducin, a G- protein, which in turn stimulates cyclicGMPphosphodiesterase •Leads to closing of an ion channel, hyperpolarization of the membrane, and a decreased rate of neurotransmitter release Vitamin A •FUNCTIONS •Vision •Photoexcited rhodopsin activates transducin, a G- protein, which in turn stimulates cyclicGMPphosphodiesterase •Leads to closing of an ion channel, hyperpolarization of the membrane, and a decreased rate of neurotransmitter release Vitamin A •FUNCTIONS •Vitamin A deficiency, in terms of the need for the resynthesis of rhodopsin

•Results in night blindness (nyctalopia) •In vitamin A deficiency

•The outer segments of the rods lose their opsin

•leading to their eventual degeneration •On a molecular basis, collagenase activity is increased in vitamin A deficiency Retinoic acid has been shown to inhibit the enzyme collagenase by forming an inactive protein complex with the liganded nuclear retinoic acid receptors Vitamin A •FUNCTIONS •Maintenance of Normal Epithelium •Protective linings on many of the body’s organs •Respiratory, gastrointestinal, and urogenital tracts, as well as the eye, are protected from environmental influences by mucous membranes •In deficiency of vitamin A, epithelial cells that make up the membrane will change their characteristic structure Vitamin A •FUNCTIONS •Maintenance of Normal Epithelium •Vitamin A plays an important role in altering permeability of lipoprotein membranes of cells and of intracellular particles •Vitamin A penetrates lipoprotein membranes and at optimum level may act as a cross-linkage agent between the lipid and protein, thus stabilizing the membrane Vitamin A •FUNCTIONS •Maintenance of Normal Epithelium •When vitamin A is deficient •Normal mucus-secreting cells of epithelium in various locations throughout the body become replaced by a stratified, keratinized epithelium •Keratinized epithelium allows pathogen entry through the skin, lung, gastrointestinal tract, and urogenital tract surface Vitamin A •FUNCTIONS •Maintenance of Normal Epithelium •When vitamin A is deficient •Regeneration of normal mucosal epithelium damaged by infection or inflammation can be impaired

• Many noninfective problems due to keratinization of epithelium, such as diarrhea •Specific interference with reproduction caused by altered epithelium •Elevated cerebrospinal fluid pressure Vitamin A •FUNCTIONS •Maintenance of Normal Epithelium •Vitamin A is necessary for the formation of large molecules containing glucosamine •Occurring in almost all tissues of mammalian organisms but principally in the mucus-secreting epithelia and in the extracellular matrix of cartilage, mainly as chondroitin sulfate Vitamin A •FUNCTIONS •Reproduction •Vit A deficiency reduce reproductive ability •Hatchability is significantly reduced •Decline in sexual activity and failure of spermatogenesis •In the female results in the resorption of the fetus, abortion, or birth of dead offspring •Retained placenta Failure to maintain healthy epithelium Vitamin A •FUNCTIONS •Bone Development •Vit A deficiency •Osteoclast (reabsorbing bone) activity is reduced •Excessive deposition of periosteal bone by the apparently unchecked function of osteoblasts (depositing bone) •Disorganized bone growth •Irritation of the joints •Constriction of the openings through which the optic and auditory nerves pass, Vitamin A •FUNCTIONS •Bone Development •Vit A deficiency •Osteoclast (reabsorbing bone) activity is reduced •Excessive deposition of periosteal bone by the apparently unchecked function of osteoblasts (depositing bone) •Disorganized bone growth •Irritation of the joints •Constriction of the openings through which the optic and auditory nerves pass, Vitamin A •FUNCTIONS Relationship to Immunological Response and Disease Conditions •Increased frequency and severity of bacterial, protozoal, and viral infections

•Is related to maintenance of mucous membranes

•Normal functioning of the adrenal gland for production of corticosteroids needed to combat disease

Vitamin A •FUNCTIONS Relationship to Immunological Response and Disease Conditions •Vitamin A deficiency affects immune function •Particularly the antibody response to T-cell–dependent antigens

•The RAR-α mRNA expression and antigen-specific proliferative responses of T lymphocytes are influenced by vitamin A status •Modulated by retinoic acid Vitamin A •FUNCTIONS Relationship to Immunological Response and Disease Conditions •Vitamin A deficiency causes decreased phagocytic activity in macrophages and neutrophils

•Intestinal IgA response is impaired by vitamin A deficiency

•Ig A system is an important first line of defense against infections of mucosal surfaces Vitamin A •FUNCTIONS Relationship to Immunological Response and Disease Conditions •Supplemental vitamin A improved the health of animals infected with roundworms

•Hens infected with Capillaria organisms

•Treating ringworm (Trichophyton verrucosum) infection in cattle Vitamin A •FUNCTIONS Relationship to Immunological Response and Disease Conditions •Vitamin A-deficient chicks •Loss of lymphocytes •Fowl typhoid (Salmonella gallinarum) • Vitamin A levels greater than the normal decreased mortality Vitamin A •FUNCTIONS Relationship to Immunological Response and Disease Conditions •Vitamin A-deficient chicks •Loss of lymphocytes •Fowl typhoid (Salmonella gallinarum) • Vitamin A levels greater than the normal decreased mortality Vitamin A

Vitamin A

Vitamin A •Effects of Deficiency •Normal vision •Maintenance of healthy epithelial or surface tissues •Normal bone development •Decreased antibody production •Impaired cell-mediated immune processes Vitamin A •Effects of Deficiency •Ruminants •Susceptibility to pinkeye or other diseases related to the mucous membranes •Keratinization lowers the resistance of the epithelial tissues

•Respiratory diseases

• Vitamin A deficiency could indirectly result from zinc deficiency •Interferes with the synthesis of retinol-binding protein Vitamin A •Effects of Deficiency •Ruminants •High calcium and low forage zinc concentrations •Slow release of liver vitamin A •In cattle •Reduced feed intake, rough hair coat, edema of the joints and brisket, lacrimation, xerophthalmia, night blindness, slow growth, blindness, low conception rates, abortion, stillbirths, blind calves, abnormal semen, reduced libido, and susceptibility to respiratory and other infections Vitamin A •Effects of Deficiency •Ruminants •High calcium and low forage zinc concentrations •Slow release of liver vitamin A •In cattle •Reduced feed intake, rough hair coat, edema of the joints and brisket, lacrimation, xerophthalmia, night blindness, slow growth, blindness, low conception rates, abortion, stillbirths, blind calves, abnormal semen, reduced libido, and susceptibility to respiratory and other infections Vitamin A •Effects of Deficiency •Poultry •Slower growth, lowered resistance to disease, eye lesions, muscular incoordination •chickens become emaciated and weak

•decrease in egg production

•length of time between clutches increases greatly •Hatchability is decreased Vitamin E •Introduction •Important •Against free-radical injury; enhancing the immune response; and playing a role in prevention of cancer, heart disease, cataracts, Parkinson’s disease •Vitamin E was discovered in 1922 by Evans and Bishop •Vitamin E was isolated as α-tocopherol •tokos meaning childbirth or offspring, the Greek pherein meaning to bring forth, and ol to designate an alcohol Vitamin E •Introduction •δ-Tocopherol was reported in 1947, and tocotrienols were described in about 1959

• Throughout the 1920s •Recognized only as a factor required for reproduction in rats • In 1931 •Vitamin E is also required for prevention of encephalomalacia in chicks and of nutritional muscular dystrophy in rabbits and guinea pigs Vitamin E •Introduction •δ-Tocopherol was reported in 1947, and tocotrienols were described in about 1959

• Throughout the 1920s •Recognized only as a factor required for reproduction in rats • In 1931 •Vitamin E is also required for prevention of encephalomalacia in chicks and of nutritional muscular dystrophy in rabbits and guinea pigs Vitamin E •Introduction •1944 •Multiplicity of clinical signs •In the chick •Exudative diathesis, encephalomalacia, and muscular dystrophy

Vitamin E •CHEMICAL STRUCTURE AND PROPERTIES •Vitamin E activity in food derives from a series of compounds of plant origin

•The tocopherols and tocotrienols •Four tocopherols (α, β, γ, and δ)

•Four tocotrienols (α, β, γ, and δ)

•6-chromanol ring structure and a side chain

Vitamin E

Vitamin E •CHEMICAL STRUCTURE AND PROPERTIES •Differences among α, β, γ, and δ are due to the placement of methyl groups on the ring

Vitamin E

Vitamin E •CHEMICAL STRUCTURE AND PROPERTIES •The difference between tocopherols and tocotrienols •Due to unsaturation of the side chain in the latter •dl-α-tocopheryl acetate •Accepted as the International Standard (1 mg = 1 international unit)

•Synthetic-free tocopherol, dl-α-tocopherol •Has a potency of 1.1 IU/mg Vitamin E •CHEMICAL STRUCTURE AND PROPERTIES •Activity of naturally occurring α-tocopherol, d-α-tocopherol •(also called RRR-tocopherol) is 1.49 IU/mg, and of its acetate, 1.36 IU/mg •α-Tocopherol, the most active compound, is fully methylated •At positions 5, 7, and 8 (2 R, 4´R, 8´R-α-tocopherol, abbreviated RRR) Vitamin E •CHEMICAL STRUCTURE AND PROPERTIES •The loss of one or both of the methyl groups at position 5 or 7 on the ring

•Reduces vitamin E activity of the structures •dl-α-Tocopheryl acetate is the most widely available source of vitamin E for supplementation •The acetate ester is very stable to in vitro oxidation •Has no activity as an in vitro antioxidant •Readily hydrolyzed in the intestine to nonesterified or free tocopherol •The potent in vivo antioxidant Vitamin E •CHEMICAL STRUCTURE AND PROPERTIES •The d form should not be referred to as “natural” as it is derived from natural

•Undergoes chemical processing (e.g., methylation and hydrogenation) •Free d- and dl-α-tocopherol as alcohol forms and their respective ester forms have the highest biopotency •Free form is easily oxidized •Stable forms such as acetate and succinate esters have been synthesized Vitamin E •CHEMICAL STRUCTURE AND PROPERTIES •Serum and certain tissue vitamin E concentrations are influenced

•Method of supplementation, dosage levels, chemical formulation, and carrier of vitamin E supplements •Sheep and cattle •d form resulted in higher serum and selected tissue α-tocopherol concentrations than the dl when administered on an equal IU basis Vitamin E •CHEMICAL STRUCTURE AND PROPERTIES •Serum and certain tissue vitamin E concentrations are influenced

•In preruminant calves and sheep •Relative IU biopotencies of d an dl form were similar

• Natural versus synthetic (important for vit E biopotency)

•Ester and carrier used is also important for vit E biopotency Vitamin E •CHEMICAL STRUCTURE AND PROPERTIES •In sheep •The natural form of d-α-tocopheryl succinate had only one - third the biopotency of the synthetic dl-α-tocopheryl acetate •Alcohol forms of vitamin E

•Higher concentrations of α-tocopherol in serum and tissues compared to ester forms •Less stable Vitamin E •CHEMICAL STRUCTURE AND PROPERTIES •From a practical viewpoint •Young ruminant may not utilize ester forms (e.g., acetate) as well as the alcohol forms of vitamin E for the first few weeks of life

Vitamin E •METABOLISM •Absorption and Transport •Vitamin E absorption •Is related to fat digestion and is facilitated by bile and pancreatic lipase

•Primary site of absorption

•Medial small intestine •No matter if it is free alcohol or esters •Most vitamin E is absorbed as the alcohol Vitamin E •METABOLISM •Absorption and Transport •Esters are largely hydrolyzed in the gut wall •Free alcohol enters the intestinal lacteals and is transported via lymph to the general circulation

•Medium-chain triglycerides particularly enhance absorption •Polyunsaturated fatty acids (PUFAs) are inhibitory Vitamin E •METABOLISM •Absorption and Transport •The tocopherol form •Is subject to destruction in the digestive tract to some extent, whereas the acetate ester is not

•Acetate is readily split off in the intestinal wall

•Alcohol is reformed and absorbed •Permitting vitamin to function as a biological antioxidant Vitamin E •METABOLISM •Absorption and Transport •Acetate form absorbed or injected into the body evidently is converted there to the alcohol form •Vitamin E in plasma

•Attached mainly to lipoproteins in the globulin fraction within cells and occurs mainly in mitochondria and microsomes •vitamin is taken up by the liver and is released in combination with low-density lipoprotein (LDL) cholesterol Vitamin E

Vitamin E •METABOLISM •Absorption and Transport •Rates and amounts of absorption of the various tocopherols and tocotrienols are in the same general order of magnitude as their biological potencies •α-Tocopherol is absorbed best, with γ-tocopherol absorption 85% that of α-forms but with a more rapid excretion Vitamin E •METABOLISM •Placental and Mammary Transfer •Vitamin E does not cross the placenta in any appreciable amounts •It is concentrated in colostrum

•Neonatal ruminants and pigs

•limited placental transport of α-tocopherol •Neonates highly susceptible to vitamin E deficiency

Vitamin E •METABOLISM •Placental and Mammary Transfer •limited placental transport of α-tocopherol •Neonates highly susceptible to vitamin E deficiency •Newborns must rely heavily on ingestion of colostrum as a source of vitamin E

•In calves and lambs •Inefficient placental transfer of vitamin E •After consumption of colostrum •high levels of the vitamin have been shown in calves Vitamin E •METABOLISM •Placental and Mammary Transfer •Importance of providing colostrum rich in vitamin E is quite apparent •Both calves and lambs are born with low levels of the vitamin

Vitamin E •METABOLISM •Storage and Excretion •Vitamin E is stored throughout all body tissues •Major sites •Adipose tissue, liver, and muscle, with highest storage in the liver

Vitamin E •METABOLISM •FUNCTIONS •Vitamin E has been shown to be essential for •Integrity and optimum function of the reproductive, muscular, circulatory, nervous, and immune systems

•Some functions of vitamin E

•Can be fulfilled in part or entirely by traces of Se or by certain synthetic antioxidants Vitamin E •METABOLISM •FUNCTIONS •The sulfur-bearing amino acids, cystine and methionine, affect certain vitamin E functions •Vitamin E as a Biological Antioxidant

•Its role as an intercellular and intracellular antioxidant

•Vitamin E is part of the body’s intracellular defense •Against the adverse effects of reactive oxygen and free radicals •Initiate oxidation of unsaturated phospholipids and critical sulfhydryl groups Vitamin E •METABOLISM •FUNCTIONS •Vitamin E functions as a quenching agent for free radical molecules with single, highly reactive electrons in their outer shells •Free radicals attract a hydrogen atom, along with its electron, away from the chain structure of a PUFA •Satisfying the electron needs of the original free radical but leaving the PUFA short one electron Vitamin E •METABOLISM •FUNCTIONS •Fatty acid free radical is formed that joins with molecular oxygen to form a peroxyl radical •Steals a hydrogenelectron unit from yet another PUFA

•This reaction can continue in a chain, resulting in the destruction of thousands of PUFA molecules •Free radicals can be extremely damaging to biological systems Vitamin E •METABOLISM •FUNCTIONS •Free radicals, including •Hydroxy, hypochlorite, peroxy, alkoxy, superoxide, hydrogen peroxide, and singlet oxygen, are generated by autoxidation or radiation, or from activities of some oxidases, dehydrogenases, and peroxidases Vitamin E •METABOLISM •FUNCTIONS •Highly reactive oxygen species •Such as superoxide anion radical (O2), hydroxyl radical (HO), hydrogen peroxide (H2O2), and singlet oxygen (O2)

•Produced in the course of normal aerobic cellular metabolism •Phagocytic granulocytes undergo respiratory burst to •produce oxygen radicals to destroy the intracellular pathogens Vitamin E •METABOLISM •FUNCTIONS •These oxidative products can, in turn, damage healthy cells if they are not eliminated •Antioxidants serve to stabilize these highly reactive free radicals, thereby maintaining the structural and functional integrity of cells •Antioxidants are very important to the immune defense and health of humans and animals

Vitamin E •METABOLISM •FUNCTIONS •Synergistic role of Se with vitamin E •Se act in aqueous cell media (cytosol and mitochondrial matrix)

•Destroying hydrogen peroxide and hydroperoxides via the enzyme glutathione peroxidase • Se is the co-factor of this enzyme •Protecting fats within the cell membrane from breaking down Vitamin E

Vitamin E •METABOLISM •FUNCTIONS •Oxidation of vitamin E •Prevents oxidation of other lipid materials to free radicals and peroxides within cell

•Protecting the cell membrane from damage

•Vitamin E reacts •As a chain-breaking antioxidant •Neutralizing free radicals and preventing oxidation of lipids within membranes Vitamin E •METABOLISM •FUNCTIONS •Free radicals •Damage their cell of origin • Migrate and damage adjacent cells •More free radicals are produced in a chain reaction leading to tissue destruction •Function of vitamin E •Interrupt production of free radicals at the initial stage Vitamin E •METABOLISM •FUNCTIONS •Vitamin E-Se deficiency •Myodystrophic tissue with leakage of cellular compounds such as creatinine and various transaminases through affected membranes into plasma •The more active the cell (e.g., the cells of skeletal and involuntary muscles) •The greater the inflow of lipids for energy supply •The greater the risk of tissue damage if vitamin E is limiting Vitamin E •METABOLISM •FUNCTIONS •Antioxidant property of vitamin E •Ensures erythrocyte stability and maintenance of capillary blood vessel integrity

•Protect or spare body supplies of such oxidizable materials as vitamin A, vitamin C, and the carotenes

Vitamin E •METABOLISM •FUNCTIONS •Certain deficiency signs of vitamin E (e.g., muscular dystrophy) •Can be prevented by diet supplementation with other antioxidants

Vitamin E •METABOLISM •FUNCTIONS •Membrane Structure and Prostaglandin Synthesis •α-Tocopherol may be involved in the formation of structural components of biological membranes

•α-tocopherol stimulated the incorporation of 14C from linoleic acid into arachidonic acid in fibroblast phospholipids •α-tocopherol exerted a pronounced stimulatory influence on •Formation of prostaglandin E from arachidonic acid Vitamin E •METABOLISM •FUNCTIONS •Blood Clotting •Inhibitor of platelet aggregation in pigs •Inhibiting peroxidation of arachidonicacid •Required for formation of prostaglandins involved in platelet aggregation Vitamin E •METABOLISM •FUNCTIONS •Disease Resistance •Antioxidant vitamins generally enhance different aspects of cellular and noncellular (humoral) immunity

•Maintaining the functional and structural integrity of important immune cells Vitamin E •METABOLISM •FUNCTIONS •Disease Resistance •Vitamin C •Regenerate the reduced form of α-tocopherol •Sparing effects of these vitamins •In process of sparing fatty acid oxidation • Tocopherol is oxidized to the tocopheryl free radical Ascorbic acid can donate an electron to the tocopheryl free radical Vitamin E •METABOLISM •FUNCTIONS •Disease Resistance •The role of vitamin E and Se in protecting leukocytes and macrophages during phagocytosis

•Vitamin E and Se may help these cells to survive the toxic products that are produced in order to effectively kill ingested bacteria

Vitamin E •METABOLISM •FUNCTIONS •Disease Resistance •Vitamin E acts as a tissue antioxidant •Any infection or other stress factors may exacerbate depletion of the limited vitamin E stores

•Stress and disease • Increase production of glucocorticoids, epinephrine, eicosanoids, and phagocytic activity Vitamin E •METABOLISM •FUNCTIONS •Disease Resistance •Stress and disease • Increase production of glucocorticoids, epinephrine, eicosanoids, and phagocytic activity

•Prominent producers of free radicals •Vitamin E has been implicated • To stimulate serum antibody synthesis, particularly IgG antibodies Vitamin E •METABOLISM •FUNCTIONS •Disease Resistance •The protective effects of vitamin E on animal health •Its role in reduction of glucocorticoids •which are known to be immunosuppressive • Immuno-enhancing effect of vitmain E •Altering arachidonic acid metabolism and subsequent synthesis of prostaglandin, thromboxanes, and leukotrienes Vitamin E •METABOLISM •FUNCTIONS •Electron Transport and Deoxyribonucleic Acid (DNA) •Vitamin E is involved in biological oxidation-reduction reactions

•Regulates the biosynthesis of DNA within cells

Vitamin E •METABOLISM •FUNCTIONS •Relationship to Toxic Elements or Substances •Vitamin E and Se provide protection against toxicity with three classes of heavy metals

• The first class

•Cadmium and mercury •Se is highly effective, but vitamin E has little influence Vitamin E •METABOLISM •FUNCTIONS •Relationship to Toxic Elements or Substances •Vitamin E and Se provide protection against toxicity with three classes of heavy metals

• Second class

•Silver and arsenic •Vitamin E is highly effective •Se is also effective but only at relatively high levels Vitamin E •METABOLISM •FUNCTIONS •Relationship to Toxic Elements or Substances •Vitamin E and Se provide protection against toxicity with three classes of heavy metals

• The third class

•Lead •Vitamin E is effective, but Se has little effect Vitamin E •METABOLISM •FUNCTIONS •Relationship with Selenium in Tissue Protection •Selenium has a sparing effect on vitamin E •Delays onset of deficiency signs •vitamin E and sulfur amino acids •Partially protect against or delay onset of several forms of Se deficiency syndromes Vitamin E •METABOLISM •FUNCTIONS •Relationship with Selenium in Tissue Protection •Diets deficient in both vitamin E and Se •Tissue breakdown in most species •Due to peroxidation Vitamin E •METABOLISM •FUNCTIONS •Relationship with Selenium in Tissue Protection •Vitamin E in cellular and subcellular membranes •The first line of defense against peroxidation of vital phospholipids

•Even with adequate vitamin E, some peroxides are formed Vitamin E •METABOLISM •FUNCTIONS •Relationship with Selenium in Tissue Protection •A second line of defense that destroys these peroxides •Enzyme glutathione peroxidase •Selenium, as part of this enzyme Vitamin E •METABOLISM •FUNCTIONS •Relationship with Selenium in Tissue Protection •Se, vitamin E, and sulfur-containing amino acids •Capable of preventing some of the same nutritional diseases

•Vitamin E prevents fatty acid hydroperoxide formation •Sulfur amino acids are precursors of glutathione peroxidase •Se is a component of glutathione peroxidase Vitamin E •METABOLISM •FUNCTIONS •Vitamin E and Se are mutually replaceable •Exceptions •Diets severely deficient in Se •vitamin E does not prevent or cure exudative diathesis Vitamin E •METABOLISM •FUNCTIONS •Normal phosphorylation •Synthesis of vitamin C •Synthesis of ubiquinone •Sulfur amino acid metabolism Vitamin E •METABOLISM •REQUIREMENTS •Minimum vitamin E requirement of normal animals and humans is approximately 30 ppm of diet •Vitamin E requirements

•Interrelationships with other dietary factors

•levels of PUFA, oxidizing agents, vitamin A, carotenoids, gossypol, or trace minerals and decreased with increasing levels of fat-soluble antioxidants, sulfur amino acids, or Se Vitamin E

Vitamin E •METABOLISM •NATURAL SOURCES •Richest sources •Vegetable oils, cereal products containing oils, eggs, and liver

Vitamin E

Vitamin E •Effects of Deficiency •Ruminants •White muscle disease (WMD; also known as nutritional muscular dystrophy) •Muscle degeneration disease in young ruminants

•Caused by Se deficiency but is influenced by vitamin E status •Occurs with two clinical patterns •A congenital type of muscular dystrophy in which young ruminants are stillborn or die within a few days of birth Vitamin E •Effects of Deficiency •Ruminants •Occurs with two clinical patterns •The second pattern (delayed WMD) develops after birth •In lambs within 3 to 6 weeks of birth but may occur as late as 4 months after birth

•In calves is generally manifested at 1 to 4 months of age Vitamin E •Effects of Deficiency •Ruminants •WMD •Weakness, stiffness, and deterioration of muscles; affected animals have difficulty standing

Vitamin E •Effects of Deficiency •Poultry •exudative diathesis •subcutaneous edema and, in severe cases, blackening of the affected parts, apathy, and inappetence

•Encephalomalacia (“crazy chick disease”)

•Characterized by ataxia, head retraction, and “cycling” with legs •Muscular dystrophy Vitamin E •Effects of Deficiency •Poultry •Exudative diathesis in chicks is a severe edema produced by a marked increase in capillary permeability •Both vitamin E and Se are involved in prevention of exudative diathesis and nutritional muscular dystrophy •In diets severely deficient in Se, however, vitamin E does not prevent or cure exudative diathesis •0.05 ppm of dietary Se completely prevents this disease Vitamin E •Effects of Deficiency •Poultry •Encephalomalacia generally affects chicks from 2 to 6 weeks of age •results from hemorrhages and edema within the cerebellum

Vitamin D •Sunshine Vitamin •It is synthesized by various materials when they are exposed to sufficient sunlight

•Two major natural sources of vitamin D

•Cholecalciferol (vitamin D3, which occurs in animals) and

ergocalciferol (vitamin D2, which occurs predominantly in plants) Vitamin D •CHEMICAL STRUCTURE, PROPERTIES, AND ANTAGONISTS •designates a group of closely related compounds that possess antirachitic activity •Supplied through the diet or by irradiation of the body

•Provitamins

•10 provitamins that, after irradiation,form compounds having variable antirachitic activity •The two most prominent members of this group are

ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) Vitamin D •CHEMICAL STRUCTURE, PROPERTIES, AND ANTAGONISTS •Ergocalciferol (ergosterol ) •Cholecalciferol (7-dehydrocholesterol)

Vitamin D

Vitamin D •CHEMICAL STRUCTURE, PROPERTIES, AND ANTAGONISTS •Ergocalciferol is derived from a common plant steroid, ergosterol, and is the usual dietary source of vitamin D •Cholecalciferol is produced exclusively from animal products. 7-Dehydrocholesterol is derived from cholesterol or squalene •Synthesized in the body and present in large amounts in skin, intestinal wall, and other tissues

Vitamin D •CHEMICAL STRUCTURE, PROPERTIES, AND ANTAGONISTS Vitamin D precursors have no antirachitic activity •Until the B-ring is opened between the 9 and 10 positions by irradiation and a double bond is formed between carbons 10 and 19 to form vitamin D • Vitamin D can be destroyed •By overtreatment with UV light and by peroxidation in the presence of rancidifying polyunsaturated fatty acids •Its oxidative destruction is increased by heat, moisture, and trace minerals Vitamin D •CHEMICAL STRUCTURE, PROPERTIES, AND ANTAGONISTS •Overirradiation of ergocalciferol or cholecalciferol produces numerous irradiation products •Tachysterols, supra-sterol1, supra-sterol2

•Some of these compounds have partial vitamin D activity, some are toxic, and some may be potent antagonists of vitamin D Vitamin D METABOLISM Absorption and Conversion from Precursors •Vitamin D obtained from the diet •Absorbed from the intestinal tract •It has also been suggested that the largest amount of dietary vitamin D is more likely to be absorbed in the ileum because of longer retention time of food in the distal portion of the intestine Vitamin D METABOLISM Absorption and Conversion from Precursors •Absorbed from the intestinal tract in association with fats, as are all the fat-soluble vitamins •Requires the presence of bile salts for absorption

•Vitamin D is absorbed with other neutral lipids via chylomicra into the lymphatic system of mammals or the portal circulation of birds and fishes •Only 50% of a dose of vitamin D is absorbed Vitamin D METABOLISM Absorption and Conversion from Precursors •Cholecalciferol is produced by irradiation of 7- ehydrocholesterol with UV light •from the sun or from an artificial source

•Cholecalciferol is synthesized in the outer skin layers

•Presence of the provitamin 7-dehydrocholesterol in the epidermis of the skin and sebaceous secretions

Vitamin D METABOLISM Absorption and Conversion from Precursors •Vitamin D is synthesized in the skin of many herbivores and omnivores, including humans, rats, pigs, horses, poultry, sheep, and cattle •little 7-dehydrocholesterol is found in the skin of cats and dogs (and likely other carnivores), and therefore little vitamin D is produced in the skin Vitamin D METABOLISM Absorption and Conversion from Precursors •exposure to sunlight, the high-energy UV photons (290–315 nm) penetrate the epidermis and photolyze 7- dehydrocholesterol (provitaminD3) to previtamin D3

•previtamin D3 undergoes a thermally induced isomerization to vitamin D3 that takes 2 to 3 days to reach completion •11 to 45 minutes of sunshine daily were sufficient to prevent rickets in growing chicks •No further improvements in growth were obtained under these conditions by adding cod liver oil Vitamin D METABOLISM Absorption and Conversion from Precursors

•During initial exposure to sunlight, provitamin D3 in the human

epidermis is efficiently converted to previtamin D3 •During initial exposure to sunlight, provitamin D3 in the human epidermis is efficiently converted to previtamin D3 •Prolonged exposure to sunlight does not significantly increase the previtamin D3 concentration above about 15% of the initial provitamin D3 concentrations Vitamin D METABOLISM Absorption and Conversion from Precursors •The cholecalciferol formed by irradiation of the 7- dehydrocholesterol in the skin •Absorbed through the skin and transported by the blood to the lipids throughout the body •Absorption can take place via skin •Once vitamin D3 is formed, it is transported in the blood

•Some of the vitamin D3 formed in and on the skin ends up in the digestive tract Vitamin D METABOLISM Conversion to Metabolically Active Forms •Vtamin D undergoes a multiple series of transformations and multi-site interactions in the living system •Whether the vitamin is ingested orally or produced photochemically in the skin, these chemical changes occur before any significant biological response is registered in the intestine or bone Vitamin D

Vitamin D METABOLISM Conversion to Metabolically Active Forms

•Once vitamin D (D2, D3, or both) enters the blood, it circulates at relatively low concentrations • In the liver

•A microsomal system hydroxylates the 25-carbon in the side chain to produce 25-OH vitamin D •Major circulating form of vitamin D under normal conditions and during vitamin D excess Vitamin D METABOLISM Conversion to Metabolically Active Forms •Conversion to 25-OHD takes place predominantly in the microsomes but also in the mitochondria •Mitochondrial enzyme is a high-capacity, low-affinity enzyme •Hydroxylate vitamin D under conditions of high substrate concentrations, such as vitamin D toxicity •The intestine and kidney can also produce 25-OHD In the chicken, the D-25-hydroxylase enzyme exists in the extrahepatic tissues, including the intestine and kidney, but in mammals, the liver is the predominant site Vitamin D METABOLISM Conversion to Metabolically Active Forms •25-OHD is then transported to the kidney on the vitamin D transport globulin •Converted to a variety of compounds, of which the most important appears to be 1,25-(OH)2D3 (calcitrol)

•Reaction occurs in the mitochondrial fraction and is catalyzed by a three-component •Mixed-function monoxygenase involving NADPH, molecular oxygen, a flavoprotein, an iron-sulfur protein,

and cytochrome P-450 (25-Hydroxyvitamin D3 1-alpha- hydroxylase (VD3 1A hydroxylase) also known as cytochrome p450 27B1 ) Vitamin D

Vitamin D METABOLISM Conversion to Metabolically Active Forms •1,25-(OH)2D that is formed in the kidney is then transported to the intestine, bones, or elsewhere in the kidney •Where it is involved in the metabolism of Ca and phosphorus (P)

•Production of 1,25-(OH)2D is very carefully regulated by parathyroid hormone in response to serum Ca and phosphate concentrations

Vitamin D METABOLISM Conversion to Metabolically Active Forms •Removal of parathyroid glands •Animal’s inability to adapt to varying Ca demands by increasing intestinal Ca absorption •Most important point of regulation of the vitamin D endocrine system occurs through the stringent control of the activity of the renal 1-hydroxylase

•Production of the hormone 1,25-(OH)2D can be modulated according to the Ca needs of the organism Vitamin D METABOLISM Conversion to Metabolically Active Forms

•Production of the hormone 1,25-(OH)2D can be modulated according to the Ca needs of the organism • Factors affect the activity of the 1-hydroxylase •Ca, parathyroid hormone, and vitamin D status

•Intestinal and serum 1,25-(OH)2D concentrations and activity of 1-hydroxylase are inversely related to dietary and serum Ca concentrations Vitamin D METABOLISM Conversion to Metabolically Active Forms •Epidermal cells (keratinocytes) •Produce vitamin D; metabolize it to its most

biologically active form, 1,25-(OH)2D; and in response

to the 1,25-(OH)2D, there is a decrease in proliferation and an increase in differentiation Vitamin D METABOLISM Conversion to Metabolically Active Forms •The kidney also converts 25-OHD to other known compounds,

including 24,25-(OH)2D, 25-26-(OH)2D, and 1,24,25-(OH)2D

•24,25-(OH)2D is responsible for the mineralization of bone and for the suppression of parathyroid hormone secretion

•24,25-(OH)2D3 is required with 1,25- (OH)2D3 for normal healing of osteomalacia in humans •24- hydroxylation appears to have a role in bone mineralization •It is also believed to be involved in the elimination pathway for 25-hydroxy and 1,25-dihydroxy vitamin D Vitamin D METABOLISM Conversion to Metabolically Active Forms •Hatchability of eggs from hens is severely depressed in vitamin

D-deficient hens even when they are fed 1,25-(OH)2D3

•1,25-(OH)2D3 is effective in maintaining blood Ca levels so that egg production and egg shell thickness remain normal •Without vitamin D, the upper mandible of the chicks fails to develop, and consequently, the chicks cannot crack the shell, resulting in mortality Vitamin D METABOLISM Transport •Vitamin D in plasma •Diet •Skin •Picked up for transport to the liver by a plasma protein called vitamin D-binding protein (DBP; also called transcalciferin) •Synthesized in the liver Vitamin D METABOLISM Transport

•In mammals, vitamin D, 25-OHD, and possibly 24,25-(OH)2D and

1,25-(OH)2D, are all transported by DBP •DBP binds 25-OHD (the major circulating metabolite) with a higher affinity than it binds vitamin D or 1,25-(OH)2D3

Vitamin D Storage and Placental Transfer •Aquatic species •Store significant amounts of vitamin D in liver •Land animals and humans do not store appreciable amounts of the vitamin •Principal stores of vitamin D •Blood and liver, lungs, kidneys •Blood has the highest concentration of vitamin D compared with other tissues Vitamin D Storage and Placental Transfer •Transplacental movement of Ca increases dramatically during the last trimester of gestation •In most mammalian species, fetal plasma Ca levels are higher than maternal levels at term •In sheep •Passive diffusion accounts for a minor component of placental Ca movement •Active transport mechanisms responsible for more than 90% Vitamin D Storage and Placental Transfer •In the pregnant rat (and perhaps humans) •1,25-(OH)2D is a critical factor in the maintenance of sufficient maternal Ca for transport to the fetus and may play a role in normal skeletal development of the neonate •No large transfer to the fetus •Liberal intake during gestation provides a sufficient store in newborns to help prevent early rickets •Newborn lambs can be provided enough in this way to meet their needs for 6 weeks Vitamin D Excretion •Excretion of absorbed vitamin D and its metabolites occurs primarily in feces with the aid of bile salts •Little vitamin D appears in urine •Metabolite 1,25-(OH)2D3-26,23-lactone may represent one of the first steps in the catabolism of 1,25-(OH)2D3

Vitamin D Function •Elevate plasma Ca and P to a level that will support normal mineralization of bone as well as other body functions •Active form of vitamin D, 1,25-(OH)2D, functions as a steroid hormone •Produced by an endocrine gland, circulated in blood bound to a carrier protein (DBP), and transported to target tissues •In the target tissue •Hormone enters the cell and binds to a cytosolic receptor or a nuclear receptor Vitamin D Function •1,25-(OH)2D regulates gene expression through its binding to tissue-specific receptors and subsequent interaction between the bound receptor and the DNA •The receptor-hormone complex moves to the nucleus •It binds to the chromatin and stimulates the transcription of particular genes to produce specific mRNAs •Code for the synthesis of specific proteins Vitamin D Function •1,25-(OH)2D regulates gene expression through its binding to tissue-specific receptors and subsequent interaction between the bound receptor and the DNA •The receptor-hormone complex moves to the nucleus •It binds to the chromatin and stimulates the transcription of particular genes to produce specific mRNAs •Code for the synthesis of specific proteins •A membrane-bound receptor, in addition to nuclear receptors, exists Vitamin D Function •Common vitamin D receptor gene alleles •Contribute to the genetic variability in bone mass and bone turnover •A heterodimer of the vitamin D receptor (VDR) and a vitamin A receptor (RXR) within the nucleus of the cell •Active complex for mediating positive transcriptional

effects of 1,25-(OH)2D Vitamin D Function •The two receptors (vitamins D and A) selectively interact •With specific hormone response elements composed of direct repeats of specific nucleotides located in the promoter of regulated genes •The complex that binds to these elements actually consists of three distinct elements •1,25-(OH)2D3 hormonal ligand •Vitamin D receptor (VDR) •Vitamin A (retinoid) X receptors (RXR) Vitamin D Function •1,25-(OH)2D3 also generates biological actions through mechanisms not dependent on regulation of gene transcription •Biological responses via signal transduction mechanisms that are independent of the nuclear VDRs •Nongenomic pathways •can include stimulation of membrane lipid turnover, 2+ activation of Ca channels, and elevation of 2+ intracellular Ca concentrations, all of which have been shown to occur within seconds after addition of

1,25-(OH)2D3 Vitamin D Relationship to Calcium and Phosphorus Homeostasis •Tetany in humans and animals results if plasma Ca levels are appreciably below normal •To control blood Ca and P levels •Two hormones—thyrocalcitonin (calcitonin) and parathyroid hormone (PTH)—function in a delicate relationship with 1,25- (OH)2D

•Production rate of 1,25-(OH)2D is under physiological control as well as dietary control

Vitamin D Relationship to Calcium and Phosphorus Homeostasis •Calcitonin, contrary to the other two •Regulates high serum Ca levels by •Depressing gut absorption •Halting bone demineralization •Reabsorption in the kidney •Vitamin D brings about an elevation of plasma Ca and P •Stimulating specific pump mechanisms in the intestine, bone,and kidney Vitamin D Relationship to Calcium and Phosphorus Homeostasis •These three sources of Ca and P thus provide reservoirs •Enable vitamin D to elevate the levels of Ca and P in blood to levels •Necessary for normal bone mineralization and for other functions ascribed to Ca Vitamin D Relationship to Calcium and Phosphorus Homeostasis •Intestinal Effects •Vitamin D stimulates active transport of Ca and P across intestinal epithelium •Stimulation involves the •Parathyroid hormone directly and the active form of vitamin D •Parathyroid hormone indirectly stimulates intestinal Ca

•Absorption by stimulating production of 1,25-(OH)2D under conditions of hypocalcemia Vitamin D Relationship to Calcium and Phosphorus Homeostasis •How Vit D Stimulates Ca and P absorption •1,25-(OH)2D is transferred to the nucleus of the intestinal cell •Interacts with the chromatin material •Specific RNAs are elaborated by the nucleus, and when these are translated into specific proteins by ribosomes, the events leading to enhancement of Ca and P absorption occur Vitamin D Relationship to Calcium and Phosphorus Homeostasis •In the intestine •1,25-(OH)2D promotes synthesis of Ca-binding protein (calbindin) and other proteins and stimulates Ca and P absorption •Vitamin D has also been reported to influence magnesium (Mg) absorption as well as Ca and P balance Vitamin D Relationship to Calcium and Phosphorus Homeostasis •In the intestine •Intestinal Ca transport relies on •Integrated effects of both genomic and nongenomic mechanisms of hormone action •Two kinds of mucosal proteins are dependent on vitamin D •Calbindin •Intestinal membrane Ca-binding protein (IMCal) Vitamin D Relationship to Calcium and Phosphorus Homeostasis •In the intestine •Intestinal Ca transport relies on •Integrated effects of both genomic and nongenomic mechanisms of hormone action •Two kinds of mucosal proteins are dependent on vitamin D •Calbindin •Intestinal membrane Ca-binding protein (IMCal) Vitamin D Relationship to Calcium and Phosphorus Homeostasis •Intestinal membrane Ca-binding protein (IMCal) •A membrane component of the translocation mechanism rather than a cytosol constituent

•Nongenomic mechanism by which 1,25-(OH)2D regulates Ca transport across the luminal membrane of the enterocyte •Inducing a specific alteration in membrane phosphatidylcholine content and structure •An increase in membrane fluidity and thereby to an increase in Ca transport rate Vitamin D Relationship to Calcium and Phosphorus Homeostasis

•Size of the villus and the microvilli increases upon 1,25-(OH)2D3 treatment •Brush border undergoes noticeable alterations in structure and composition of cell surface proteins and lipids

2+ •Corresponding to the increase in Ca transport mediated by

1,25-(OH)2D3 •1,25-(OH)2D3 has been shown to increase levels of several other proteins in the intestinal mucosa •Alkaline phosphatase, Ca-stimulated ATPase, and phytase enzyme activities

Vitamin D Relationship to Calcium and Phosphorus Homeostasis •Once Ca transported to basolateral membrane •It is extruded from the cell against a 1,000-fold concentration gradient by Mg-dependent Ca-ATPase, which is also increased

by 1,25-(OH)2D3 Vitamin D Relationship to Calcium and Phosphorus Homeostasis Bone effects •Mineralization of bone as well as demineralization or mobilization of bone mineral •1,25-(OH)2D is one of the factors •Controlling the balance between bone formation and resorption •In young animals during bone formation •Minerals are deposited on the matrix •Accompanied by an invasion of blood vessels gives rise to trabecular bone andcauses bones toelongate Vitamin D Relationship to Calcium and Phosphorus Homeostasis Bone effects •Minerals are deposited on the matrix •Accompanied by an invasion of blood vessels gives rise to trabecular bone andcauses bones toelongate •Vitamin D deficiency •Organic matrix fails to mineralize,causing rickets in the young and osteomalacia in adults Vitamin D Relationship to Calcium and Phosphorus Homeostasis Bone effects

•1,25- (OH)2D3 •Mineralization of the bone matrix, and localized in the nuclei of bone cells • Vit D •Mobilization of Ca from bone to the extracellular fluid compartment •Function is shared by PTH Vitamin D Relationship to Calcium and Phosphorus Homeostasis Bone effects •Vit D •Mobilization of Ca from bone to the extracellular fluid compartment •Function is shared by PTH •An active process requiring metabolic energy •Transports Ca and phosphate across the bone membrane by acting on osteocytes and osteoclasts Vitamin D Relationship to Calcium and Phosphorus Homeostasis Bone effects •Vit D •Rapid, acute plasma Ca regulation is •Due to the interaction of plasma Ca with Ca-binding sites in bone mineral since blood is in contact with bone •Changes in plasma Ca •Brought about by a change in the proportion of high- and low-affinity Ca-binding sites •Access to which is regulated by osteoclasts and osteoblasts, respectively Vitamin D Relationship to Calcium and Phosphorus Homeostasis Bone effects •Respond to hormonal signals by shape changes •Contraction of osteoclasts and corresponding expansion of osteoblasts make more high-affinity sites available •Decrease in the blood Ca level •Osteoblast contraction and osteoclast expansion •An increase in the blood Ca level Vitamin D Relationship to Calcium and Phosphorus Homeostasis Bone effects •Vit D •Biosynthesis of collagen in preparation for mineralization •Vitamin D deficiency causes inadequate cross-linking of collagen as a result of low lysyl oxidase activity Vitamin D Kidney Effects •Vitamin D •Functions in the distal renal tubules to improve Ca reabsorption and is mediated by calbindin •99% of the filtered load of Ca is reabsorbed in the absence of vitamin D and the parathyroid hormone •1,25-(OH)2D3 functions in improving renal reabsorption of Ca •With intact parathyroids and without vitamin D •renal tubular resorption of inorganic phosphate decreases •increasing phosphate clearance and resulting in hypophosphatemia Vitamin D Calcium and Phosphorus Absorption by Ruminants •Sheep and cattle absorb Ca from their gut according to •Need and that they can alter the efficiency of absorption to meet a change in requirement •An increase in both absorption and efficiency of absorption also occurs •In mature sheep when their requirement for Ca is increased through pregnancy or lactation or after a period of Ca deficiency Vitamin D Calcium and Phosphorus Absorption by Ruminants •The efficiency of absorption of Ca in the small intestine of the dairy cow

•Rise in response to a reduction in dietary Ca intake and to the onset of lactation •Calcium absorption has also been shown to be directly related to milk production •In early lactation, when the demand for Ca is greatest • The increase in absorption falls short of the requirement, with the deficit being met by increased bone resorption Vitamin D Calcium and Phosphorus Absorption by Ruminants •Mechanism by which Ca is adjusted in response to requirement •A fall in plasma Ca concentration resulting from an increase in demand •Leads in turn to an increase in parathyroid hormone release •Stimulates the increased production by the kidney of

1,25-(OH)2D •Acts on the gut to increase the production of calbindin and so accelerates Ca absorption Vitamin D Calcium and Phosphorus Absorption by Ruminants •Mechanism by which Ca is adjusted in response to requirement •An increase in plasma Ca concentration •Causes suppression of parathyroid hormone release

•A reduction in 1,25-(OH)2D production, and reduced Ca absorption Vitamin D Phosphorus Absorption •In sheep, control of P balance must therefore be achieved within the gut through control of either absorption or secretion or both

•Saliva is the main contributor of P in the gut •Upper small intestine is the major absorptive site •Secretion of P in saliva has usually been viewed in the context of its role as a buffer against the volatile fatty acids produced in the rumen •Salivary glands, may also play an important role in P homeostasis by controlling the amount of P secreted into the gut Vitamin D Phosphorus Absorption •Ruminants have a higher renal threshold for P excretion than do monogastric species

•Poor-quality roughage diets, apart from their low digestibility, also tend to contain little P •The ratio between the amount of P required for saliva production and dietary intake is wide •If the renal threshold for P excretion in ruminants were as low as in monogastric species •when the concentration of inorganic P in the plasma rises in response to reabsorption, P would be excreted in the urine Vitamin D Phosphorus Absorption •This P would not, however, in any real sense be surplus to requirement, and its loss would have to be met from a diet low in available P •an advantage to the ruminant in maintaining the high renal threshold for P excretion •Concentrate diets, especially those that include fish meal, contain much larger quantities of P than do roughage diets •Intake may equal or exceed the amount secreted in the saliva •A different level of control may operate •Increasing dietary P intake leads to increased absorption and increased urinary P excretion Vitamin D Phosphorus Absorption •1,25- (OH)2D has also been suggested as a possible regulator of intestinal P absorption in ruminants

Vitamin D Other Vitamin D Functions •Relate to biochemical changes occurring in the intestine, bone, and kidney

•Required for chick embryonic development •Vitamin D treatment stimulated yolk Ca mobilization •The vitamin D-dependent Ca-binding protein, calbindin, is present in the yolk sac

•Hormonal action of 1,25-(OH)2D on yolk sac Ca transport is mediated by the regulated expression and activity of calbindin Vitamin D Other Vitamin D Functions •1,25-(OH)2D is also essential for the transport of eggshell Ca to the embryo across the chorioallantoic membrane

•In the pancreas •1,25-(OH)2D is essential for normal insulin secretion •1,25-(OH)2D3 are recognized as being involved in regulation of the growth and differentiation of a variety of cell types, including those of hematopoietic and immune systems •1,25-(OH)2D3 as an immunoregulatory hormone •A significant 70% enhancement of lymphocyte proliferation in cells treated with pokeweed mitogen Vitamin D Other Vitamin D Functions •1,25-(OH)2D3 also inhibits growth of certain malignant cell types and promotes their differentiation

•Inhibit proliferation of leukemic cells, breast cancer cells, and colorectal cancer cells •A deficiency of vitamin D may promote prostate cancer

Vitamin D REQUIREMENTS •In addition to sunlight, other factors influencing dietary vitamin D requirements include (1) amount and ratio of dietary Ca and P, (2) availability of P and Ca, (3) species, and (4) physiological factors •Vitamin D becomes a nutritionally important factor in the absence of sufficient sunlight •Sunlight is more potent in the tropics than in the temperate or arctic zones •in summer than in winter •More potent at noon than in the morning or evening, and more potent at high altitudes Vitamin D REQUIREMENTS •Sunlight provides most of its antirachitic powers during the 4 hours around noon

•Air pollution •The incidence of rickets became widespread in industrial cities •Rickets has been called the first air-pollution disease •The colors of the coat and skin •UV irradiation is more effective on exposed skin than through a heavy coat of hair •Irradiation is less effective on dark pigmented skin Vitamin D REQUIREMENTS •Aging can decrease more than twofold the capacity of the skin to produce previtamin D3

•Amounts of dietary Ca and P, and the physical and chemical forms in which they are presented •High dietary Ca concentrations can precipitate phosphates as insoluble Ca phosphate •Ca is given in the form of a relatively insoluble compound, or a Ca compound that is normally easily soluble but is too coarsely ground, it may be comparatively unavailable; coarse limestone (Ca carbonate) Vitamin D REQUIREMENTS •Soluble Ca salts are more readily absorbed, and oxalates tend to interfere with absorption

• Some of this interference can be overcome by dietary vitamin D or irradiation •P of inorganic orthophosphate tends to be well absorbed •Phytic acid •The predominant P compound of unprocessed cereal grains and oilseeds, seems to be poorly available •Except to species(such as ruminants) with massive populations of microorganisms in the gut that synthesize phytase enzymes Vitamin D REQUIREMENTS •Phosphorus absorption is mostly independent of vitamin D intake •Improvement upon vitamin administration being a result of improving Ca absorption •Need for vitamin D depends to a large extent on the Ca-P ratio •Ratio becomes either wider or narrower than the optimum, the vitamin D requirement increases •Dietary dry matter of rapidly growing young stock should contain approximately 0.6 to 1.2% Ca •Ca-P ratio in the range of about 1.2:1 to 1.5:1 Vitamin D REQUIREMENTS •Intestinal pH as well as other dietary nutrients influence Ca and P requirements and Vit D •Fermentation of excess carbohydrates •Intestinal contents more acid, which favors both Ca and P absorption •By converting less soluble alkaline salts to the more soluble acid salts Vitamin D REQUIREMENTS •High intakes of fats containing higher fatty acids increase highly insoluble Ca soaps •Potassium may increase P absorption •Cations that form insoluble phosphates such as iron and aluminum interfere Vitamin D

Vitamin D NATURAL SOURCES

Vitamin D REQUIREMENTS •For all but a few species, vitamin D2 and vitamin D3 are equally potent •In poultry, other birds, and a few of the rarer mammals, including some New World monkeys, •Vitamin D3 has been found to be many times more potent than D2 on a weight basis •For poultry •Vitamin D3 may be 30 times more effective than D2 Vitamin D DEFICIENCY •Rickets, generally characterized by a decreased concentration of Ca and P in the organic matrices of cartilage and bone •In the adult, osteomalacia •Cartilage growth has ceased, is characterized by a decreased concentration of Ca and P in the bone matrix •Osteoporosis •Decrease in the amount of bone, leading to fractures after minimal trauma •Bone mineral and protein matrix are lost, resulting in less overall bone but normal composition Vitamin D DEFICIENCY •Osteomalacia is also characterized by inadequate bone mineralization •In contrast to osteoporosis, persons with osteomalacia have normal protein matrix that is not fully mineralized •Inhibited growth, weight loss, and reduced or lost appetite before characteristic signs that relate primarily to the bone system become apparent Vitamin D DEFICIENCY •Ruminants •Decreased appetite and growth rate, digestive disturbances, ricketsstiffness in gait, labored breathing, irritability, weakness, and occasionally tetany and convulsions •Milk fever (parturient paresis) •Paralyzing metabolic disease caused by hypocalcemia near parturition and initiation of lactation in high milk-producing dairy cows Vitamin D DEFICIENCY •Ruminants •Milk fever (parturient paresis) •Related to Ca status, previous Ca intake, and malfunction of

the hormone form of vitamin D [1,25-(OH)2D] and PTH •Serum Ca decreases from a normal 8 to 10 mg/dL to 3 to 7 mg/dL (average, 5 mg/dL) Vitamin D DEFICIENCY •Ruminants •Milk fever (parturient paresis) •Aged cows are at the greatest risk •Heifers almost never develop milk fever •Older animals have a decreased response to dietary Ca stress •Both decreased production of 1,25- (OH)2D and decreased response to the 1,25-(OH)2D

Vitamin D DEFICIENCY •Ruminants •Milk fever (parturient paresis) •Target tissues of cows with milk fever may have defective hormone receptors •the number of receptors declines with age •In older animals •Fewer osteoclasts exist to respond to hormone stimulation •Delays the ability of bone to contribute Ca to the plasma Ca pool Vitamin D DEFICIENCY •Ruminants

•Milk fever (parturient paresis) •Aging process is also associated with reduced renal 1α-ydroxylase response to Ca stress, therefore reducing the amount of 1,25- OH)2D produced from 25-OHD