Abstract

The goal of this investigation is to explore the metabolism of ursodeoxycholic acid and related bile acids in animals. A major objective will deal with the pathway for the transformation of chenodeoxycholic acid into ursodeoxycholic acid by both intestinal bacteria and hepatic enzymes. The demonstration that ursodeoxycholic acid is the major bile acid in the nutria (M. coypus) provides an animal model to study the hepatic pathway. Pure strains of C. absonum will be used to study the bacterial for- mation of ursodeoxycholic acid from 7-ketolithocholic acid and 3alpha-hydroxy-5beta-chol-6-en-24-oic acid. In addition, the specificity and pathway of bacterial 7-dehydroxylation of chenodeoxycholic acid and ursodeoxycholic acid will be examined with the use of pure strains of Eubacterium spp. V.P.I. 12708. The role of 3alpha-hydroxy-5beta-chol-6-en-24-oic acid and 3alpha- hydroxy-5beta-chol-7-en-24-oic acid as intermediates will be considered as well as the role of amino acid conjugation in hindering 7-dehydroxylation. Also, we will synthesize conjugates of ursodeoxycholic acid with analogs of taurine and glycine that resist bacterial deconjugation, study the mechanism of bacterial resistance and also the effect of these analogs on cholesterol and bile acid synthesis in the rat. Finally, we will study the effect of 7alpha-and 7beta-hyvdroxy bile acids on the regulation of bile acid synthesis in the rat.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK018707-12
Application #
3226121
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1977-07-01
Project End
1992-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
12
Fiscal Year
1988
Total Cost
Indirect Cost

  Institution

Name
University of Medicine & Dentistry of NJ
Department
Type
Schools of Medicine
DUNS #
605799469
City
Newark
State
NJ
Country
United States
Zip Code
07107

  Publications

Xu, G; Elsey, R M; Lance, V A et al. (1997) A study on biliary ductal system and bile fistula in the American alligator, Alligator mississippiensis. J Exp Zool 279:554-61
Tint, G S; Batta, A K; Xu, G et al. (1997) The Smith-Lemli-Opitz syndrome: a potentially fatal birth defect caused by a block in the last enzymatic step in cholesterol biosynthesis. Subcell Biochem 28:117-44
Cobb, M M; Salen, G; Tint, G S (1997) Comparative effect of dietary sitosterol on plasma sterols and cholesterol and bile acid synthesis in a sitosterolemic homozygote and heterozygote subject. J Am Coll Nutr 16:605-13
Pauli, R M; Williams, M S; Josephson, K D et al. (1997) Smith-Lemli-Opitz syndrome: thirty-year follow-up of ""S"" of ""RSH"" syndrome. Am J Med Genet 68:260-2
Honda, M; Tint, G S; Honda, A et al. (1996) Measurement of 3 beta-hydroxysteroid delta 7-reductase activity in cultured skin fibroblasts utilizing ergosterol as a substrate: a new method for the diagnosis of the Smith-Lemli-Opitz syndrome. J Lipid Res 37:2433-8
Honda, A; Tint, G S; Shefer, S et al. (1996) Effect of YM 9429, a potent teratogen, on cholesterol biosynthesis in cultured cells and rat liver microsomes. Steroids 61:544-8
Cobb, M M; Salen, G; Tint, G S et al. (1996) Sitosterolemia: opposing effects of cholestyramine and lovastatin on plasma sterol levels in a homozygous girl and her heterozygous father. Metabolism 45:673-9
Batta, A K; Salen, G (1996) Characterization of the biochemical abnormality in the Smith-Lemli-Opitz syndrome. Indian J Pediatr 63:143-7
Honda, A; Tint, G S; Salen, G et al. (1995) Defective conversion of 7-dehydrocholesterol to cholesterol in cultured skin fibroblasts from Smith-Lemli-Opitz syndrome homozygotes. J Lipid Res 36:1595-601
Xu, G; Salen, G; Shefer, S et al. (1995) Unexpected inhibition of cholesterol 7 alpha-hydroxylase by cholesterol in New Zealand white and Watanabe heritable hyperlipidemic rabbits. J Clin Invest 95:1497-504

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