Our objective is to develop new gallstone-dissolving agents which are more effective and safer than the bile acids currently in use, namely, chenodeoxycholic acid and ursodeoxycholic acid. Since the 7-methyl substituted 3,7-dihydroxy and 3,7,12-trihydroxy cholanoic acids are not readily 7-dehydroxylated by the intestinal flora and are known to participate in the enterohepatic circulation, these and related compounds merit further investigation. It is therefore proposed to synthesize and characterize new bile acid analogs with alkyl substituents in the 7- (or 6-) position. The biological stability of the new compounds will be studied in mixed fecal cultures and in pure cultures of fecal bacteria. The metabolism of the bile acid analogs (absorption, biotransformation, conjugation, enterohepatic cycling, fecal and urinary excretion) will be examined in the hamster and prairie dog and compared with the metabolism of the naturally occurring bile acids. The effect of the new compounds on cholesterol/bile acid metabolism and on bile composition will be observed in the isolated, perfused prairie dog liver and in the hamster. The toxicity of the bile acid analogs will be evaluated in the hamster and prairie dog (acute and chronic) and in the rabbit which is known to be highly sensitive to 3,7-dihydroxy bile acids and lithocholic acid. Compounds with appropriate properties will be evaluated further in the prairie dog model of cholesterol cholelithiasis to assess their efficacy in the prevention and dissolution of cholesterol gallstones. The studies will aid not only in the development of new and useful drugs for eventual use in man but will elucidate structure-function relationships in the bile acid series, specifically those relating to modifications of cholesterol/bile acid/biliary lipid metabolism. It is further proposed to evaluate a new hamster model of pigment cholelithiasis recently discovered by the applicant. This model employs a nutritionally adequate, semipurified diet containing 0.3% cholesterol. The effect of dietary modifications on the formation, and composition of the stones will be investigated and correlated with bile composition and cholesterol metabolism.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL024061-13
Application #
3485806
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1978-12-01
Project End
1991-11-30
Budget Start
1990-12-15
Budget End
1991-11-30
Support Year
13
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Beth Israel Medical Center (New York)
Department
Type
DUNS #
075255364
City
New York
State
NY
Country
United States
Zip Code
10003
Ohshima, A; Cohen, B I; Ayyad, N et al. (1996) Dietary fat alters biliary lipid secretion in the hamster. Lipids 31:949-54
Ohshima, A; Cohen, B I; Ayyad, N et al. (1996) Effect of castration and hormonal supplementation on cholesterol cholelithiasis in the male hamster. Lipids 31:945-8
Ayyad, N; Cohen, B I; Ohshima, A et al. (1996) An improved ultracentrifugation method for the separation of cholesterol carriers in bile. Lipids 31:657-60
Mikami, T; Kihira, K; Ikawa, S et al. (1996) Effect of some sulfonate analogues of ursodeoxycholic acid on biliary lipid secretion in the rat. J Lipid Res 37:1181-8
Mikami, T; Ohshima, A; Mosbach, E H et al. (1996) 15 alpha-hydroxylation of a bile acid analogue, sodium 3 alpha,7 alpha-dihydroxy-25,26-bishomo-5 beta-cholane-26-sulfonate in the hamster. J Lipid Res 37:1189-97
Ayyad, N; Cohen, B I; Ohshima, A et al. (1996) Prevention of cholesterol cholelithiasis by dietary unsaturated fats in hormone-treated female hamsters. Lipids 31:721-7
Ohshima, A; Cohen, B I; Ayyad, N et al. (1996) Effect of a synthetic androgen on biliary lipid secretion in the female hamster. Lipids 31:879-86
Cohen, B I; Mikami, T; Ayyad, N et al. (1995) Hydrophilic bile acids: prevention and dissolution experiments in two animal models of cholesterol cholelithiasis. Lipids 30:855-61
Cohen, B I; Mikami, T; Ayyad, N et al. (1995) Dietary fat alters the distribution of cholesterol between vesicles and micelles in hamster bile. Lipids 30:299-305
Ayyad, N; Cohen, B I; Mosbach, E H et al. (1995) Hormonal control of cholesterol cholelithiasis in the female hamster. J Lipid Res 36:1483-8

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