03. VITAMIN B6 19/1/07 07:17 Página 7 Nutr Hosp. 2007;22(1):7-24 ISSN 0212-1611 • CODEN NUHOEQ S.V.R. 318 Revisión Vitamin B6 status, deficiency and its consequences - an overview A. Spinneker**, R. Sola*, V. Lemmen*,**, M. J. Castillo*, K. Pietrzik** and M. González-Gross*,**,*** *Grupo Effects 262. Facultad de Medicina. Universidad de Granada. Spain. **Institut für Ernährungs- und Lebensmittelwis- senschaften, Rheinische Friedrichs-Wilhelms Universität Bonn. Germany. ***Facultad de Ciencias de la Actividad Física y del Deporte. Universidad Politécnica de Madrid. Spain. Abstract ESTADO DE VITAMINA B6, DEFICIENCIA Y SUS CONSECUENCIAS — UNA REVISIÓN Background: Vitamin B6 is thought to be a most versa- tile coenzyme that participates in more than 100 bioche- mical reactions. It is involved in amino acid and ho- Resumen mocysteine metabolism, glucose and lipid metabolism, Antecedentes: se piensa que la vitamina B es la coenzi- neurotransmitter production and DNA/RNA synthesis. 6 Vitamin B can also be a modulator of gene expression. ma más versátil que participa en más de 100 reacciones 6 bioquímicas. Está implicada en el metabolismo de los Nowadays, clinically evident vitamin B6 deficiency is not a common disorder, at least in the general population. aminoácidos y de la homocisteína, el metabolismo de la Nevertheless, a subclinical, undiagnosed deficiency may glucosa y los lípidos, en la producción de neurotransmi- be present in some subjects, particularly in the elderly. sores y en la síntesis de ADN/ARN. Esta vitamina tam- Objective: This review gives a complete overview over bién puede ser un modulador de la expresión génica. the metabolism and interactions of vitamin B . Further, Hoy en día, la deficiencia clínicamente evidente de vita- 6 mina B no es una afección habitual, al menos en la po- we show which complications and deficiency symptoms 6 blación general. Sin embargo, puede ocurrir una defi- can occur due to a lack of vitamin B6 and possibilities for public health and supplemental interventions. ciencia subclínica no diagnosticada en algunos Methods: The database Medline (www.ncvi.nlm.nih.gov) individuos, especialmente en los ancianos. Objetivo: esta revisión aporta una visión de conjunto was searched for terms like “vitamin B6”, “pyridoxal”, “cancer”, “homocysteine”, etc. For a complete understan- completa sobre el metabolismo y las interacciones de la vitamina B . Además, mostramos qué complicaciones y ding, we included studies with early findings from the for- 6 ties as well as recent results from 2006. These studies were síntomas por deficiencia pueden ocurrir por la falta de vitamina B y las posibilidades de intervenciones de sa- summarised and compared in different chapters. 6 Results and conclusion: In fact, it has been proposed lud pública y de suplementos. that suboptimal vitamin B status is associated with cer- Métodos: se buscó en la base de datos Medline 6 (www.ncvi.nlm.nih.gov) con los términos “vitamin B ”, tain diseases that particularly afflict the elderly popula- 6 tion: impaired cognitive function, Alzheimer’s disease, “pyridoxal”, “cancer”, “homocysteine”, etc. Para una cardiovascular disease, and different types of cancer. So- mayor comprensión, incluimos estudios con hallazgos me of these problems may be related to the elevated ho- iniciales de los años cuarenta, así como estudios recientes del año 2006. Se resumieron estos estudios y se compara- mocysteine concentrations associated to vitamin B6 defi- ciency, but there is also evidence for other mechanisms ron por capítulos diferentes. independent of homocysteine by which a suboptimal vi- Resultados y conclusión: de hecho, se ha propuesto que el estado sub-óptimo de vitamina B6 se asocia con tamin B6 status could increase the risk for these chronic diseases. ciertas enfermedades que afligen en especial a la pobla- ción anciana: función cognitiva alterada, enfermedad de (Nutr Hosp. 2007;22:7-24) Alzheimer, cardiopatía y distintos tipos de cáncer. Algu- Key words: Vitamin B . Coenzyme. Elderly. Homocystei- nos de estos problemas podrían relacionarse con concen- 6 traciones elevadas de homocisteína asociadas con una ne. Vitamin B6 deficiency. deficiencia de vitamina B6, pero también existe la eviden- cia de otros mecanismos independientes de la homociste- ína por los que un estado sub-óptimo de vitamina B6 po- Correspondence: Prof. Dr. Marcela González-Gross dría aumentar el riesgo de padecer estas enfermedades Facultad de CC de la Actividad Física y del Deporte crónicas. Universidad Politécnica de Madrid Martín Fierro, s/n 28040 Madrid (Nutr Hosp. 2007;22:7-24) E-mail: [email protected] Palabras clave: Vitamina B6. Coenzima. Anciano. Homocis- Recibido: 15-XI-2006. teína. Deficiencia de vitamina B6. Aceptado: 10-XII-2006. 7 03. VITAMIN B6 10/1/07 07:45 Página 8 Introduction and pyridoxamin-5´-phosphate (PMP) are the biologi- cal active coenzyme forms (fig. 1). They are water-so- Vitamin B6 sufficiency is required for optimal he- luble and can be inter-converted in normal human me- alth. This is due to the participation in many different tabolism1. PLP is the major form that is used by biochemical reactions. Vitamin B6 and its derivatives pyridoxine-dependent enzymes. These enzymes ca- are needed, especially in there coenzyme functions, talyse more than 100 essential biochemical reactions for the main metabolic pathways in the human body. in human metabolism. For that reason, it is clear that a vitamin B6 deficiency, B6 vitamers are similarly absorbed in the upper je- even in mild forms, has effects on the human metabo- junum and little in ileum, but before absorption, lism. Several diseases and impairments of health are phosphate esters must be hydrolysed by alkaline connected to the wide variety of B6 functions in su- phosphatase or other intestinal phosphatases. The boptimal status. This can also be worsened through non-phosphorylated form enters the mucosal cells by ageing. two different processes according to luminal concen- This article gets deep into metabolic functions of tration. At low concentrations, vitamers enter the cell vitamin B6 and gives an overview about associated di- by an active process regulated by requirements. At seases to vitamin B6 deficiency with new insights high concentrations, transport is by non-saturable pas- from recently published studies, including prevention sive diffusion mechanisms1. Once in the cell, vitamers and treatment potentials. are phosphorylated by ATP dependent pyridoxine ki- nase in a process referred to as metabolic trapping. The phosphorylated form can not traverse cell mem- Vitamin B6 – Chemistry, metabolism and branes and must therefore be dephosphorylated again bioavailability before traversing the basolateral membrane side of the mucosal cell. Once in the circulation, most of B6 vita- Vitamin B6 comprises a group of three related 3-hy- mers are transported to the liver where they are again droxy-2-methyl-pyrimidine derivatives. The derivati- phosphorylated to PNP, PLP or PMP, and then relea- 1,2 ve pyridoxine (PN) is an alcohol, pyridoxal (PL) is an sed to plasma . Vitamin B6 in plasma is mainly PLP aldehyde and pyridoxamine (PM) contains an amino (60%), PN (15%) and PL (14%). These vitamers cir- group. Their respective 5´-phosphate esters: pyridoxi- culate bound to albumin1. In peripheral tissues, in or- ne 5´-phosphate (PNP), pyridoxal 5´-phosphate (PLP) der to cross cell membranes, the phosphorylated Fig. 1.—Metabolic inter- conversion of pyridoxine, pyridoxal, pyridoxamine and their respective phosp- hate esters (modified after Bässler, 2002). 8 Nutr Hosp. 2007;22(1):7-24 A. Spinneker y cols. 03. VITAMIN B6 10/1/07 07:45 Página 9 forms need to be dephosphorylated by alkaline phosp- enables the amino acid for further reactions. Some of horylase. Transport into tissue cells is by gradient dif- the reactions PLP is involved in are: transamination of fusion. This gradient is maintained thanks to the im- amino acids to keto acids (which can be then used for mediate rephosphorylation occurring inside the cells. gluconeogenesis), formation of α-aminolevuline acid Intracellular accumulation of PLP seems to be limited (a precursor of heme group), as coenzyme in serin- by intracellular protein binding capacity. In circula- palmityl-transferase (implicated in sphingomyelin tion, PLP may enter red blood cells where PLP synthesis), decarboxylation of L-amino acids (to yield bounds to haemoglobin. In red cell mass, PLP is at amines, which function as neurotransmitters, hormo- higher concentration (4 to 5 times) than in plasma. nes or biogenic amines). In the nervous system, PN- PLP increases the oxygen affinity of haemoglobin3. dependent enzymes fall into two categories: transami- Total body stores of B6 have been estimated to be as nases and L-amino acid decarboxylases. The crucial little as 167 mg4. Up to 80% of that amount is found in PLP-dependent steps of the synthesis of several neu- muscle tissue2. PLP in metabolism occurs mainly in rotransmitters are: the enzymatic decarboxylation of the liver where it is oxidized to 4-pyridoxic-acid (4- 3,4-dihydroxyphenylalanine (DOPA) to dopamine, PA) which is released and excreted. Almost 50% of the conversion of tryptophan to both nitric acid and α urinary vitamin B6 is 4-PA. In total, some 2 mg vita- serotonine, and the conversion of glutamic acid to - 10 min B6 can be excreted every day. In cases of B6 defi- aminobutyric-acid (GABA) . Another important me- ciency, excretion appears to be lower. PN is also ex- tabolic pathway is the metabolism of one-carbon creted in faeces but to a limited extent and can units. One-carbon (methyl) units, usually obtained therefore be neglected4. from serine, are transferred to tetrahydrofolate (THF) Gregory has reviewed the bioavailability of vitamin yielding 5,10-methylene-tetrahydrofolate (5,10- 5 B6 . In a diet typically containing about 15% PN glu- methylene-THF). This reaction is catalysed by serine- coside, which is about 50% as bioavailable as the ot- hydroxymethyltransferase (SHMT), a PLP dependent her vitamers, vitamin B6 is about 75% bioavailable.