THE METABOLISM OF URSODEOXYCHOLIC ACID IN MAN

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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.