Abstract

It is proposed to synthesize analogs of the cholelitholytic bile acids, chenodeoxycholic acid and ursodeoxycholic acid, in order to develop new compounds with increased resistance to degradation by the intestinal bacterial flora and hepatic enzymes, increased cholelitholytic activity and reduced hepatoxicity. The biological stability of the bile acid analogs, and their inhibitory effect on the bacterial 7-dehydroxylase, will be examined in cultures of fecal bacteria and with purified bacterial 7-dehydroxylase. Resistance to hepatic degradation will be studied in the isolated perfused rabbit liver. Analogs with adequate biologic stability and significant biliary excretion will be tested in animal models of cholesterol cholelithiasis (hamster, squirrel monkey). It is proposed to identify structural features of known bile acids and analogs associated with specific effects on the prevension or regression of gallstones, and on several parameters of cholesterol bile acid metabolism (cholesterol balance, rate-limiting enzymes of cholesterol metabolism (HMG-CoA reductase, cholesterol 7Alpha-hydroxylase) biliary lipids and bile acids, tissue sterol levels and composition of gallstones).

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL024061-08
Application #
3337484
Study Section
(GCN)
Project Start
1978-12-01
Project End
1986-11-30
Budget Start
1985-12-01
Budget End
1986-11-30
Support Year
8
Fiscal Year
1986
Total Cost
Indirect Cost

  Institution

Name
Beth Israel Medical Center (New York)
Department
Type
DUNS #
075255364
City
New York
State
NY
Country
United States
Zip Code
10003

  Publications

Mikami, T; Kihira, K; Ikawa, S et al. (1993) Metabolism of sulfonate analogs of ursodeoxycholic acid and their effects on biliary bile acid composition in hamsters. J Lipid Res 34:429-35
Kihira, K; Mikami, T; Ikawa, S et al. (1992) Synthesis of sulfonate analogs of bile acids. Steroids 57:193-8
Yoshii, M; Mosbach, E H; Schteingart, C D et al. (1991) Chemical synthesis and hepatic biotransformation of 3 alpha,7 alpha-dihydroxy-7 beta-methyl-24-nor-5 beta-cholan-23-oic acid, a 7-methyl derivative of norchenodeoxycholic acid: studies in the hamster. J Lipid Res 32:1729-40
Mildvan, D; Buzas, J; Armstrong, D et al. (1991) An open-label, dose-ranging trial of AL 721 in patients with persistent generalized lymphadenopathy and AIDS-related complex. J Acquir Immune Defic Syndr 4:945-51
Kihira, K; Okamoto, A; Ikawa, S et al. (1991) Metabolism of sodium 3 alpha,7 alpha-dihydroxy-5 beta-cholane-24-sulfonate in hamsters. J Biochem 109:879-81
Une, M; Yamanaga, K; Mosbach, E H et al. (1990) Metabolism of 7 beta-alkyl chenodeoxycholic acid analogs and their effect on cholesterol metabolism in hamsters. J Lipid Res 31:1015-21
Schmassmann, A; Hofmann, A F; Angellotti, M A et al. (1990) Prevention of ursodeoxycholate hepatotoxicity in the rabbit by conjugation with N-methyl amino acids. Hepatology 11:989-96
Cohen, B I; Mosbach, E H; Matoba, N et al. (1990) The effect of alfalfa-corn diets on cholesterol metabolism and gallstones in prairie dogs. Lipids 25:143-8
Cohen, B I; Matoba, N; Mosbach, E H et al. (1990) Bile acids substituted in the 6 position prevent cholesterol gallstone formation in the hamster. Gastroenterology 98:397-405
Matoba, N; Cohen, B I; Mosbach, E H et al. (1989) 7-Methyl bile acids: effects of chenodeoxycholic acid, cholic acid, and their 7 beta-methyl analogues on the formation of cholesterol gallstones in the prairie dog. Gastroenterology 96:178-85

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