ROLE OF INTESTINAL BACTERIA IN STEROID METABOLISM

我们的目标是开发新的胆石溶解剂， 比目前使用的胆汁酸更有效和安全，即， 鹅去氧胆酸和熊去氧胆酸。 由于7-甲基 取代的3，7-二羟基和3，7，12-三羟基胆烷酸不 容易被肠道植物群7-脱羟基，并且已知 参与肠肝循环，这些和相关化合物 值得进一步调查。 因此，建议综合和 表征在7-（或 6-)位置 新化合物的生物稳定性将是 在混合粪便培养物和粪便细菌的纯培养物中进行了研究。 胆汁酸类似物的代谢（吸收，生物转化， 结合、肝肠循环、粪便和尿液排泄）将被 在仓鼠和草原土拨鼠中进行了检查，并与 天然胆汁酸 新化合物对 将观察胆固醇/胆汁酸代谢和胆汁组成 在离体灌流的草原土拨鼠肝脏和仓鼠肝脏中。 的 将在仓鼠中评价胆汁酸类似物的毒性， 草原犬鼠（急性和慢性）和兔子，这是已知的， 对3，7-二羟基胆汁酸和石胆酸高度敏感。 具有适当性质的化合物将在本说明书中进一步评价。 胆固醇胆石症的草原犬模型，以评估它们在 预防和溶解胆固醇结石。 这些研究将 不仅有助于开发新的和有用的药物， 但将阐明胆汁酸的结构-功能关系 系列，特别是与胆固醇/胆汁修饰相关的系列 酸/胆汁脂质代谢。 还建议评价一项新的 仓鼠模型的色素胆石症最近发现的 申请人。 这种模式采用营养充足的半纯化饮食 含有0.3%的胆固醇 饮食调整对 形成，和组成的石头将被调查， 与胆汁成分和胆固醇代谢有关。

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.