DOCSLIB.ORG

The Metabolism of Desmosterol in Human Subjects During Triparanol Administration

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Metabolism of Desmosterol in Human Subjects During Triparanol Administration THE METABOLISM OF DESMOSTEROL IN HUMAN SUBJECTS DURING TRIPARANOL ADMINISTRATION DeWitt S. Goodman, … , Joel Avigan, Hildegard Wilson J Clin Invest. 1962;41(5):962-971. https://doi.org/10.1172/JCI104575. Research Article Find the latest version: https://jci.me/104575/pdf Journal of Clinical Investigation Vol. 41, No. 5, 1962 THE METABOLISM OF DESMOSTEROL IN HUMAN SUBJECTS DURING TRIPARANOL ADMINISTRATION * BY DEWITT S. GOODMAN, JOEL AVIGAN AND HILDEGARD WILSON (From the Section on Metabolism, National Heart Institute, and the National Institute of Arthritis and Metabolic Diseases, Bethesda, Md.) (Submitted for publication October 25, 1961; accepted January 25, 1962) Recent studies with triparanol (1-[p-,3-diethyl- Patient G.B. was a 55 year old man with known arterio- aminoethoxyphenyl ]-1- (p-tolyl) -2- (p-chloro- sclerotic heart disease and mild hypercholesterolemia; phenyl)ethanol) have demonstrated that this com- since 1957 he had maintained a satisfactory and stable cardiac status. At the time of the present study he had pound inhibits cholesterol biosynthesis by blocking been taking 250 mg triparanol daily for 4 weeks, and had the reduction of 24-dehydrocholesterol (desmos- a total serum sterol level in the high normal range. terol) to cholesterol (2-4). Administration of Patient F.A. was a 40 year old man with a 4- to 5-year triparanol to laboratory animals and to man re- history of gout and essential hyperlipemia. At the time sults in of of this study he had been on an isocaloric low purine diet the accumulation desmosterol in the for several weeks, and both the gout and hyperlipemia plasma and tissues, usually with some concom- were in remission. He received 250 mg triparanol daily itant lowering of the plasma total sterol concen- for 2 weeks prior to the start of this study. tration (2, 5). In studies with human subjects Design of study. Each study was begun in the fasting it was observed that after about 2 weeks the des- patient by the rapid injection of 20 /Ac of 2-C14-mevalonic mosterol concentration tended to plateau at an acid, in isotonic saline, into an antecubital vein. Patient F.A. also received, in the same injection, 20 jsc of 7-a H'- average level of 27 per cent of the total circulating cholesterol, previously incorporated into his own serum sterols (5). The ratios of desmosterol to cho- lipoproteins by the method of Avigan (6). Blood sam- lesterol in animal tissues (2) differed somewhat ples were collected 3 hours later from the opposite ante- from the ratios in plasma. In addition, injection of cubital vein, and at varying intervals thereafter. We ob- the cholesterol precursor 2-C14-mevalonic acid dur- tained bile in the early mornings by duodenal intubation, employing intravenous cholecystokinin when necessary, ing triparanol administration resulted in the rapid to ensure an adequate sample, and also collected 24-hour appearance of labeled desmosterol in blood, while urine samples, using small amounts of toluene as pre- no significant radioactivity appeared in cholesterol servative. in the first few days (5). Serum sterols. Sera were extracted with 25 vol of The object of the present experiments was to alcohol: acetone, 1: 1 (vol/vol), and the free sterols were precipitated from these extracts as their digitonide com- study the metabolism of desmosterol in patients plexes. After collection of the digitonide precipitates, the receiving triparanol. Since cholesterol serves as supernatants were saponified with ethanolic KOH, neu- the biosynthetic precursor for several physiologi- tralized with acetic acid, and the hydrolyzed ester sterols cally important compounds, including bile acids were precipitated as digitonides. The sterol digitonides and steroid hormones, the question arose whether thus derived from the free and ester sterol fractions desmosterol could also function as a precursor for were then washed, cleaved with pyridine, and the sterols extracted, washed, and dried as described by Steinberg, these compounds without first being transformed Avigan and Feigelson (5). The sterol fractions so ob- into cholesterol. The studies reported herein dem- tained, consisting of mixtures of desmosterol and choles- onstrate the direct conversion of desmosterol to terol, will subsequently be referred to as unfractionated both bile acids and to steroid hormones, and also free or ester sterols. Small portions of the unfractionated information sterols were used for the measurement of cholesterol and provide about the over-all metabolism desmosterol in the sample, by the differential colori- of this sterol in the triparanol-treated man. metric method of Avigan and co-workers (2). Other portions of the sterols were directly assayed for radio- EXPERIMENTAL activity, and the specific radioactivities were determined. Clinical material. Both of the patients studied were The remaining unfractionated sterols of each sample hospitalized on a metabolic ward of the Clinical Center. were separated into cholesterol and desmosterol by chro- matography of their p-phenylazobenzoyl esters on col- * Presented in part at the First International Pharma- umns of silicic acid: Celite, 2: 1 (2). The purified cho- cology Meeting, Stockholm, Sweden, August, 1961 (1). lesterol and desmosterol fractions were then individually 962 DESMOSTEROL METABOLISM DURING TRIPARANOL 963 assayed for radioactivity and were also colorimetrically oids were obtained from the 24-hour urine samples by analyzed for cholesterol and desmosterol. Cholesterol incubation of the urine with p-glucuronidase, followed by was usually obtained free of desmosterol, but the des- acidification, continuous ether extraction for 72 hours, mosterol samples were generally contaminated with small and appropriate washings of the ether extract to re- amounts of cholesterol. As discussed elsewhere, how- move acids and phenolic compounds (11, 12). In the ever (5), by knowing the analytical values for the puri- first study (Patient G.B.), the neutral extract was then fied sterols in the samples counted, it was possible to directly oxidized with chromic acid (CrO3) solution by calculate with precision the individual specific radioac- a slightly modified procedure of Wotiz, Lemon and tivities of cholesterol and desmosterol, despite the con- Marcus (13). The CrO3 oxidation converts most corti- tamination of the desmosterol samples with small amounts sol metabolites to etiocholanetrione; the other metabo- of cholesterol. An internal check on the accuracy of lites giving significant amounts of this product are the these determinations was provided by the specific radio- C1903 steroids (e.g., 1 1-hydroxyetiocholanolone). This activity measurements of the unfractionated sterols. The procedure, consequently, provided enough of a single calculated and measured values for specific radioactivity compound for accurate determination of specific radio- of the unfractionated sterols agreed closely in all cases. activity. The excess CrO3 was reduced with 0.2 per Bile. Bile samples were extracted with 25 vol of cent NaHSO3 and the steroids extracted with methylene ethanol. Each ethanol extract was evaporated nearly to chloride. This extract was washed with 0.1 N NaOH dryness and saponified with NaOH under pressure. The and with water, and then prepared for paper chromatog- unsaponifiable fraction was then extracted with ethyl raphy. ether, followed by acidification of the sample and extrac- In the second study (Patient F.A.) the entire extract tion of the acidic fraction with ethyl ether. Cholic acid of each urine was first subjected to partition column was purified from the acidic fraction of the bile of Pa- chromatography as described elsewhere (11), with a tient G.B. by reversed-phase partition chromatography, column of 15 g aluminum silicate and 50 per cent with methanol-water as moving phase and isooctanol- ethanol as stationary phase. The elution sequence was chloroform as stationary phase, as described by Norman simplied so that only two fractions were collected: 1) (7) and Sjovall (8). A mixture of chenodeoxy- and 200 ml 15 per cent chloroform in hexane; and 2) 260 deoxycholic acids was purified from the acidic fractions ml 30 per cent chloroform in hexane, followed by 120 ml of the bile samples of Patient F.A. by partition chroma- 50 per cent chloroform in hexane. The first fraction tography as described by Mosbach, Zomzely and Ken- contained all C,,O2 and C,903 (and any C2,04) steroids; dall (9), with acetic acid on Celite as stationary phase the second fraction contained all C2105 and C210A metabo- and isopropyl ether-petroleum ether mixtures as mobile lites present (i.e., all the cortisol metabolites and little phase. The amount of purified bile acid obtained was de- or nothing else). Paper chromatograms run on aliquots termined by weighing the material after crystallization of both fractions showed that in all cases the column had and drying; verification of these values was secured by effected the desired separation. These spot tests also spectrophotometric analyses of aliquots of the samples by proved that the patient was excreting the normal ma- the method of Mosbach, Kalinsky, Halpern and Kendall jor steroid metabolites in his urine. Thus the cortisol (10). The specific radioactivity of the bile acids was metabolite fraction included both THF and THE; the obtained by radioassay of a measured aliquot of the C390, steroids present included 11-ketoetiocholanolone, 11- purified sample. hydroxyetiocholanolone (in lesser amounts), and 11-hy- In some samples sterols were precipitated from the droxyandrosterone; the C1902 steroids were represented unsaponifiable fraction of bile as their digitonide com- by a band corresponding to etiocholanolone and andros- plexes, analyzed colorimetrically, and counted to deter- terone (which would not separate in the system used). mine specific radioactivity. Each column fraction from the urine samples of Pa- Urinary steroids.' Ether extracts of the neutral ster- tient F.A. was then subjected to chromic acid oxidation, 1 as described above, followed by paper chromatography of Trivial names of the steroids used in this paper fol- The oxidized steroid fractions, ex- THF: the oxidized steroids. low. Etiocholanetrione: etiocholane-3,11,17-trione.
Load more

Recommended publications
  • • Our Bodies Make All the Cholesterol We Need. • 85 % of Our Blood
    • Our bodies make all the cholesterol we need. • 85 % of our blood cholesterol level is endogenous • 15 % = dietary from meat, poultry, fish, seafood and dairy products. • It's possible for some people to eat foods high in cholesterol and still have low blood cholesterol levels. • Likewise, it's possible to eat foods low in cholesterol and have a high blood cholesterol level SYNTHESIS OF CHOLESTEROL • LOCATION • All tissues • Liver • Cortex of adrenal gland • Gonads • Smooth endoplasmic reticulum Cholesterol biosynthesis and degradation • Diet: only found in animal fat • Biosynthesis: primarily synthesized in the liver from acetyl-coA; biosynthesis is inhibited by LDL uptake • Degradation: only occurs in the liver • Cholesterol is only synthesized by animals • Although de novo synthesis of cholesterol occurs in/ by almost all tissues in humans, the capacity is greatest in liver, intestine, adrenal cortex, and reproductive tissues, including ovaries, testes, and placenta. • Most de novo synthesis occurs in the liver, where cholesterol is synthesized from acetyl-CoA in the cytoplasm. • Biosynthesis in the liver accounts for approximately 10%, and in the intestines approximately 15%, of the amount produced each day. • Since cholesterol is not synthesized in plants; vegetables & fruits play a major role in low cholesterol diets. • As previously mentioned, cholesterol biosynthesis is necessary for membrane synthesis, and as a precursor for steroid synthesis including steroid hormone and vitamin D production, and bile acid synthesis, in the liver. • Slightly less than half of the cholesterol in the body derives from biosynthesis de novo. • Most cells derive their cholesterol from LDL or HDL, but some cholesterol may be synthesize: de novo.
    [Show full text]
  • Cholesterol Metabolites 25-Hydroxycholesterol and 25-Hydroxycholesterol 3-Sulfate Are Potent Paired Regulators: from Discovery to Clinical Usage
    H OH metabolites OH Review Cholesterol Metabolites 25-Hydroxycholesterol and 25-Hydroxycholesterol 3-Sulfate Are Potent Paired Regulators: From Discovery to Clinical Usage Yaping Wang 1, Xiaobo Li 2 and Shunlin Ren 1,* 1 Department of Internal Medicine, McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23249, USA; [email protected] 2 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; [email protected] * Correspondence: [email protected]; Tel.: +1-(804)-675-5000 (ext. 4973) Abstract: Oxysterols have long been believed to be ligands of nuclear receptors such as liver × recep- tor (LXR), and they play an important role in lipid homeostasis and in the immune system, where they are involved in both transcriptional and posttranscriptional mechanisms. However, they are increas- ingly associated with a wide variety of other, sometimes surprising, cell functions. Oxysterols have also been implicated in several diseases such as metabolic syndrome. Oxysterols can be sulfated, and the sulfated oxysterols act in different directions: they decrease lipid biosynthesis, suppress inflammatory responses, and promote cell survival. Our recent reports have shown that oxysterol and oxysterol sulfates are paired epigenetic regulators, agonists, and antagonists of DNA methyl- transferases, indicating that their function of global regulation is through epigenetic modification. In this review, we explore our latest research of 25-hydroxycholesterol and 25-hydroxycholesterol 3-sulfate in a novel regulatory mechanism and evaluate the current evidence for these roles. Citation: Wang, Y.; Li, X.; Ren, S. Keywords: oxysterol sulfates; oxysterol sulfation; epigenetic regulators; 25-hydroxysterol; Cholesterol Metabolites 25-hydroxycholesterol 3-sulfate; 25-hydroxycholesterol 3,25-disulfate 25-Hydroxycholesterol and 25-Hydroxycholesterol 3-Sulfate Are Potent Paired Regulators: From Discovery to Clinical Usage.
    [Show full text]
  • Genetic Deletion of Abcc6 Disturbs Cholesterol Homeostasis in Mice Bettina Ibold1, Janina Tiemann1, Isabel Faust1, Uta Ceglarek2, Julia Dittrich2, Theo G
    www.nature.com/scientificreports OPEN Genetic deletion of Abcc6 disturbs cholesterol homeostasis in mice Bettina Ibold1, Janina Tiemann1, Isabel Faust1, Uta Ceglarek2, Julia Dittrich2, Theo G. M. F. Gorgels3,4, Arthur A. B. Bergen4,5, Olivier Vanakker6, Matthias Van Gils6, Cornelius Knabbe1 & Doris Hendig1* Genetic studies link adenosine triphosphate-binding cassette transporter C6 (ABCC6) mutations to pseudoxanthoma elasticum (PXE). ABCC6 sequence variations are correlated with altered HDL cholesterol levels and an elevated risk of coronary artery diseases. However, the role of ABCC6 in cholesterol homeostasis is not widely known. Here, we report reduced serum cholesterol and phytosterol levels in Abcc6-defcient mice, indicating an impaired sterol absorption. Ratios of cholesterol precursors to cholesterol were increased, confrmed by upregulation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase (Hmgcr) expression, suggesting activation of cholesterol biosynthesis in Abcc6−/− mice. We found that cholesterol depletion was accompanied by a substantial decrease in HDL cholesterol mediated by lowered ApoA-I and ApoA-II protein levels and not by inhibited lecithin-cholesterol transferase activity. Additionally, higher proprotein convertase subtilisin/kexin type 9 (Pcsk9) serum levels in Abcc6−/− mice and PXE patients and elevated ApoB level in knockout mice were observed, suggesting a potentially altered very low-density lipoprotein synthesis. Our results underline the role of Abcc6 in cholesterol homeostasis and indicate impaired cholesterol metabolism as an important pathomechanism involved in PXE manifestation. Mutations in the adenosine triphosphate-binding cassette transporter C6 (ABCC6) gene are responsible for pseudoxanthoma elasticum (PXE), a metabolic disease, hallmarked by a progressive elastic fber calcifcation of the skin, eyes and cardiovascular system.
    [Show full text]
  • University Microfilms, Inc., Ann Arbor, Michigan ADRENOCORTICAL STEROID PROFILE IN
    This dissertation has been Mic 61-2820 microfilmed exactly as received BESCH, Paige Keith. ADRENOCORTICAL STEROID PROFILE IN THE HYPERTENSIVE DOG. The Ohio State University, Ph.D., 1961 Chemistry, biological University Microfilms, Inc., Ann Arbor, Michigan ADRENOCORTICAL STEROID PROFILE IN THE HYPERTENSIVE DOG DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of the Ohio State University By Paige Keith Besch, B. S., M. S. The Ohio State University 1961 Approved by Katharine A. Brownell Department of Physiology DEDICATION This work is dedicated to my wife, Dr. Norma F. Besch. After having completed her graduate training, she was once again subjected to almost social isolation by the number of hours I spent away from home. It is with sincerest appreciation for her continual encouragement that I dedi­ cate this to her. ACKNOWLEDGMENTS I wish to acknowledge the assistance and encourage­ ment of my Professor, Doctor Katharine A. Brownell. Equally important to the development of this project are the experience and information obtained through the association with Doctor Frank A. Hartman, who over the years has, along with Doctor Brownell, devoted his life to the development of many of the techniques used in this study. It is also with extreme sincerity that I wish to ac­ knowledge the assistance of Mr. David J. Watson. He has never complained when asked to work long hours at night or weekends. Our association has been a fruitful one. I also wish to acknowledge the encouragement of my former Professor, employer and good friend, Doctor Joseph W.
    [Show full text]
  • Vitamin D Receptor Promotes Healthy Microbial Metabolites
    www.nature.com/scientificreports OPEN Vitamin D receptor promotes healthy microbial metabolites and microbiome Ishita Chatterjee1, Rong Lu1, Yongguo Zhang1, Jilei Zhang1, Yang Dai 2, Yinglin Xia1 ✉ & Jun Sun 1 ✉ Microbiota derived metabolites act as chemical messengers that elicit a profound impact on host physiology. Vitamin D receptor (VDR) is a key genetic factor for shaping the host microbiome. However, it remains unclear how microbial metabolites are altered in the absence of VDR. We investigated metabolites from mice with tissue-specifc deletion of VDR in intestinal epithelial cells or myeloid cells. Conditional VDR deletion severely changed metabolites specifcally produced from carbohydrate, protein, lipid, and bile acid metabolism. Eighty-four out of 765 biochemicals were signifcantly altered due to the Vdr status, and 530 signifcant changes were due to the high-fat diet intervention. The impact of diet was more prominent due to loss of VDR as indicated by the diferences in metabolites generated from energy expenditure, tri-carboxylic acid cycle, tocopherol, polyamine metabolism, and bile acids. The efect of HFD was more pronounced in female mice after VDR deletion. Interestingly, the expression levels of farnesoid X receptor in liver and intestine were signifcantly increased after intestinal epithelial VDR deletion and were further increased by the high-fat diet. Our study highlights the gender diferences, tissue specifcity, and potential gut-liver-microbiome axis mediated by VDR that might trigger downstream metabolic disorders. Metabolites are the language between microbiome and host1. To understand how host factors modulate the microbiome and consequently alter molecular and physiological processes, we need to understand the metabo- lome — the collection of interacting metabolites from the microbiome and host.
    [Show full text]
  • Phytosterols and Cholesterol in Malignant and Benign Breast Tumors1
    [CANCER RESEARCH 37, 3034-3036. September 1977] Phytosterols and Cholesterol in Malignant and Benign Breast Tumors1 Margot J. Mellies, Terry T. Ishikawa, Charles J. Glueck, and John D. Crissman Lipid Research and General Clinical Research Centers [M. J. M., T. T. I., C. J. G.j and the Department of Pathology [J. D. C], University of Cincinnati, College of Medicine, Cincinnati. Ohio 45267 SUMMARY of phytosterols in the tissue and plasma was endogenous or exogenous. No direct analyses of the tissue phytosterol and Tissue phytosterol and cholesterol levels in 10 benign and cholesterol content of normal breast or benign breast tu 8 malignant breast tumors were quantitated to reexamine mors were made as controls (3). Subsequently, in 1969, Day the hypothesis that malignant tumors had distinctive phy ef al. (1) examined tissue from 8 women with breast carci tosterol content. Phytosterols were present in 9 of 10 be noma, finding "traces of substances with retention times nign and 7 of 8 malignant breast tumors. Mean (±S.E.) similar to those of the phytosterols reported to be present cholesterol, campesterol, stigmasterol, and 0-sitosterol in by Gordan" in 1 subject. No data on normal breast tissue or malignant and benign tumors (^9/9 wet weight) did not benign adenomas were presented. The hypothesis of Gor significantly differ (p > 0.1): dan ef al, (3) and Day ef a/. (1) of distinctive phytosterol content in malignant tumors has not been further evaluated Cholesterol Campesterol Stigmasterol /3-Sitosterol in the 10-year interval since its proposal, so that neither Malignant 756 ±244 13 ±9 10 ±6 17 ±9 validation nor nonconfirmation are available.
    [Show full text]
  • ラッ ト肝 の Steroid 5Β-Reductase 活性 に 対す る酢酸第 二水銀
    〔614〕 ラ ッ ト肝 の steroid 5β-reductase 活 性 に 対 す る酢 酸 第 二 水 銀 の 影 響 The Effect of Mercuric Acetate on the Activity of Steroid 5β-reductase in the Rat Liver 北海道大学医学部衛生学教室 富 田 勤 ・佐 藤 敏 雄 ・高 桑 栄 松 北海道大学大学院環境科学研究科環境医学教室 斎 藤 和 雄 Tsutomu Tomita, Toshio Sato and Eimatsu Takakuwa Department of Hygiene and Preventive Medicine, Hokkaido University School of Medicine, Sapporo Kazuo Saito Department of Environmental Medicine, Graduate School of Environmental Science, Hokkaido University, Sapporo The increase of urinary δ-aminolevulinic acid in man and animals exposed to high concentration of mercury is studied, but the mechanism of the increase has not been clearly explained. In this paper, the content of 5β type steroid, inducing δ-aminolevulinic acid synthetase, was studied by noticing the activities of steroid 5β-reductase, which is the rate limiting enzyme in metabolism of steroid hormones, 3α- and 3β-hydroxysteroid dehydrogenase. For measurement of these activities, 105,000×g supernatant of rat liver was used. The testosterone and ⊿4-androstene-3, 17-dione 5β-reductase activities decreased on either the fourth or eleventh day after either intraperitoneal or subcutaneous administration of mercuric acetate, respe- ctively, and the adrenosterone 5β-reductase activity increased on the eleventh day after the subcutaneous administration of mercuric acetate. These changes mentioned above, however, were not significant. The progesterone and 17α-hydroxy progesterone 5β-reductase activities decreased on either the fourth or eleventh day after either intraperitioneal or subcutaneous administration of mercuric acetate, but there were no significant changes.
    [Show full text]
  • Oligodendroglial Energy Metabolism and (Re)Myelination
    life Review Oligodendroglial Energy Metabolism and (re)Myelination Vanja Tepavˇcevi´c Achucarro Basque Center for Neuroscience, University of the Basque Country, Parque Cientifico de la UPV/EHU, Barrio Sarriena s/n, Edificio Sede, Planta 3, 48940 Leioa, Spain; [email protected] Abstract: Central nervous system (CNS) myelin has a crucial role in accelerating the propagation of action potentials and providing trophic support to the axons. Defective myelination and lack of myelin regeneration following demyelination can both lead to axonal pathology and neurode- generation. Energy deficit has been evoked as an important contributor to various CNS disorders, including multiple sclerosis (MS). Thus, dysregulation of energy homeostasis in oligodendroglia may be an important contributor to myelin dysfunction and lack of repair observed in the disease. This article will focus on energy metabolism pathways in oligodendroglial cells and highlight differences dependent on the maturation stage of the cell. In addition, it will emphasize that the use of alternative energy sources by oligodendroglia may be required to save glucose for functions that cannot be fulfilled by other metabolites, thus ensuring sufficient energy input for both myelin synthesis and trophic support to the axons. Finally, it will point out that neuropathological findings in a subtype of MS lesions likely reflect defective oligodendroglial energy homeostasis in the disease. Keywords: energy metabolism; oligodendrocyte; oligodendrocyte progenitor cell; myelin; remyeli- nation; multiple sclerosis; glucose; ketone bodies; lactate; N-acetyl aspartate Citation: Tepavˇcevi´c,V. Oligodendroglial Energy Metabolism 1. Introduction and (re)Myelination. Life 2021, 11, Myelination is the key evolutionary event in the development of higher vertebrates. 238.
    [Show full text]
  • United States Patent Office Patented Jan
    3,164,611 United States Patent Office Patented Jan. 5, 1965 1. 2 reaction, care must be taken in applying this method 3,164,611 to the oxidation of heat sensitive compounds. OXDATION OF PRIMARY AND SECONDARY AL COHOLS TO THE CORRESPONDING CARBONY These organic base-chromium trioxide complexes are CSCMPOUNDS (USNG A TERTARY AMENE particularly useful oxidizing agents for effecting the oxida (CERORySSJR, TROXDE COMPLEX tion of alcohols having at least one hydrogen atom at Lewis H. Sarett, Friscetos, N.J., assigaor to Merck & Co., tached to the carbon atom bearing the hydroxyl sub Inc., Rahway, N.J., a corporatioia of New Jersey Stituent, i.e., primary and secondary alcohols, to the No Drawing. Fied any 26, 1956, Ser. No. 686,463 corresponding carbonyl compounds. Thus, primary al 13 Caias. (C. 260-349.9) cohols are oxidized to aldehydes, and secondary alcohols IO are converted to ketones. This invention relates to a novel process for the oxida This method of oxidizing alcohols to the corresponding tion of chemical compounds, and more particularly to carbonyl compounds is generally applicable to all pri an improved method for the oxidation of primary and mary and secondary alcohols. Examples of such al Secondary alcohols to the corresponding carbonyl com cohols that might be mentioned are aliphatic alcohols pounds. 5 such as alkanals, alkenols, alkinois, polyhydric alkanols, This application is a continuation-in-part application polyhydric alkenols and polyhydric alkinols; aralkyl al of my application Serial No. 263,016, filed December cohols; aralkenyl alcohols; aralkinyl alcohols; alicyclic 22, 1951, now abandoned, and my copending application alcohols such as cycloalkyl, cycloalkenyl, cycloalkinyl, Serial No.
    [Show full text]
  • Amino Acid Lipids and Uses Thereof
    (19) & (11) EP 2 494 993 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 05.09.2012 Bulletin 2012/36 A61K 48/00 (2006.01) A61K 47/06 (2006.01) A61K 9/127 (2006.01) C12N 15/88 (2006.01) (2006.01) (2006.01) (21) Application number: 12158867.7 C07C 279/14 C07D 213/40 C07D 233/26 (2006.01) C12N 15/11 (2006.01) (22) Date of filing: 02.05.2008 (84) Designated Contracting States: • Houston, Michael AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Sammamish, WA Washington 98074 (US) HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT • Harvie, Pierrot RO SE SI SK TR Bothell, WA Washington 98011 (US) Designated Extension States: • Adami, Roger AL BA MK RS Bothell, WA Washington 98012 (US) • Fam, Renata (30) Priority: 04.05.2007 US 916131 P Kenmore, WA Washington 98028 (US) 29.06.2007 US 947282 P • Prieve, Mary 02.08.2007 US 953667 P Lake Forest Park, WA Washington 98155 (US) 14.09.2007 US 972590 P • Fosnaugh, Kathy 14.09.2007 US 972653 P Bellevue, WA Washington 98008 (US) 22.01.2008 US 22571 P • Seth, Shaguna Bothell, WA Washington 98012 (US) (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: (74) Representative: Srinivasan, Ravi Chandran 08747568.7 / 2 157 982 J A Kemp 14 South Square (71) Applicant: Marina Biotech, Inc. Gray’s Inn Bothell, WA 98021-7266 (US) London WC1R 5JJ (GB) (72) Inventors: Remarks: • Quay, Steven This application was filed on 09-03-2012 as a Woodinville, WA Washington 98072 (US) divisional application to the application mentioned under INID code 62.
    [Show full text]
  • SSIEM Classification of Inborn Errors of Metabolism 2011
    SSIEM classification of Inborn Errors of Metabolism 2011 Disease group / disease ICD10 OMIM 1. Disorders of amino acid and peptide metabolism 1.1. Urea cycle disorders and inherited hyperammonaemias 1.1.1. Carbamoylphosphate synthetase I deficiency 237300 1.1.2. N-Acetylglutamate synthetase deficiency 237310 1.1.3. Ornithine transcarbamylase deficiency 311250 S Ornithine carbamoyltransferase deficiency 1.1.4. Citrullinaemia type1 215700 S Argininosuccinate synthetase deficiency 1.1.5. Argininosuccinic aciduria 207900 S Argininosuccinate lyase deficiency 1.1.6. Argininaemia 207800 S Arginase I deficiency 1.1.7. HHH syndrome 238970 S Hyperammonaemia-hyperornithinaemia-homocitrullinuria syndrome S Mitochondrial ornithine transporter (ORNT1) deficiency 1.1.8. Citrullinemia Type 2 603859 S Aspartate glutamate carrier deficiency ( SLC25A13) S Citrin deficiency 1.1.9. Hyperinsulinemic hypoglycemia and hyperammonemia caused by 138130 activating mutations in the GLUD1 gene 1.1.10. Other disorders of the urea cycle 238970 1.1.11. Unspecified hyperammonaemia 238970 1.2. Organic acidurias 1.2.1. Glutaric aciduria 1.2.1.1. Glutaric aciduria type I 231670 S Glutaryl-CoA dehydrogenase deficiency 1.2.1.2. Glutaric aciduria type III 231690 1.2.2. Propionic aciduria E711 232000 S Propionyl-CoA-Carboxylase deficiency 1.2.3. Methylmalonic aciduria E711 251000 1.2.3.1. Methylmalonyl-CoA mutase deficiency 1.2.3.2. Methylmalonyl-CoA epimerase deficiency 251120 1.2.3.3. Methylmalonic aciduria, unspecified 1.2.4. Isovaleric aciduria E711 243500 S Isovaleryl-CoA dehydrogenase deficiency 1.2.5. Methylcrotonylglycinuria E744 210200 S Methylcrotonyl-CoA carboxylase deficiency 1.2.6. Methylglutaconic aciduria E712 250950 1.2.6.1. Methylglutaconic aciduria type I E712 250950 S 3-Methylglutaconyl-CoA hydratase deficiency 1.2.6.2.
    [Show full text]
  • Studies on the Hormonal Regulation of Bile Acid Synthesis
    Department of Endocrinology, Metabolism and Diabetes, Department of Medicine Karolinska University Hospital Huddinge, and Center for Nutrition and Toxicology, NOVUM, Karolinska Institutet, Stockholm, Sweden STUDIES ON THE HORMONAL REGULATION OF BILE ACID SYNTHESIS Thomas Lundåsen Stockholm 2007 ______________________________________________________________________ All previously published papers were reproduced with permission from the publishers. Published and printed by Karolinska University Press Box 200, SE-171 77 Stockholm, Sweden © Thomas Lundåsen, 2006 ISBN 91-7357-053-2 2 T. Lundåsen ____________________________________________________________________________________ ABSTRACT The maintenance of a normal turnover of cholesterol is of vital importance, and disturbances of cholesterol metabolism may result in several important disease conditions. The major route for the elimination of cholesterol from the body is by hepatic secretion of cholesterol and bile acids (BAs) into the bile for subsequent fecal excretion. A better understanding of how hepatic cholesterol metabolism and BA synthesis are regulated is therefore of fundamental clinical importance, particularly for the prevention and treatment of cardiovascular disease. In the current thesis, the roles of known and newly recognized hormones in the regulation of BA synthesis were studied with the aim to broaden our understanding of how extrahepatic structures regulate BA synthesis in the liver. In normal humans, circulating levels of the intestinal fibroblast growth factor 19 (FGF19) were related to the amount of BAs absorbed from the intestine. The results support the concept that intestinal release of FGF19 signals to the liver suppressing BA synthesis. Thus, in addition to the liver - which harbors the full machinery for regulation of BA synthesis - the transintestinal flux of BAs is one important factor in this regulation.
    [Show full text]