The bile acids are a set of acidic steroids made from cholesterol in the liver. They serve several important physiologic functions. Their formation is the principal mechanism for cholesterol degradation; their secretion in bile is a major driving force for bile water formation; their detergency solubilizes bile lipids and the products of lipolysis in the gut. At the same time, bile acids are potentially toxic substances; toxic effects of bile acids are especially evident when they accumulate in excess in patients with cholestasis. The capacity of individual bile acids to subserve these functions and to produce toxicity is affected by their physical chemical properties; specifically, correlations with function and toxicity have been made with bile acid hydrophilicity-hydrophobicity. The hydrophobic-hydrophilic balance is maintained in part through the process of bile acid synthesis. In addition, however, the balance is maintained by post-synthetic mechanisms, ie. mechanisms of bile acid biotransformation. An understanding of these processes is importance not only in relation to bile acids, but also as a model of the biotransformation of other endo- and of xenobiotics. The set of bile acids is diverse. In addition to the conventional bile acids found in the bile of normal individuals, atypical bile acids of conventional size (eg. bile acids with a hydroxyl group in the six position of the steroid ring), short-chain bile acids, and other bile acid sub-sets have been defined. Certain of these, while present in only minute amounts in the normal individual, accumulate in excess in patients with cholestasis. Moreover, while bile acid conjugation with amino acids has been a well explored metabolic pathway, bile acid hydroxylation, sulfation, glucuronidation have been examined only preliminarily. Much of this work has been performed during the recent past in this laboratory. It is now proposed to pursue experimental directions opened to us by our previous studies. For these experiments the wide range of bile acids and bile acid conjugates synthesized, purified and characterized during the preceding grant period will be employed. Work performed on the enzymology of Phase I and II reactions of bile acids will be amplified. Enzymes involved in bile acid biotransformations will be identified, isolated, and characterized. Several of these will be cloned and expressed. The developmental pattern, induction, and polymorphic expression of certain of these enzymes will be defined. Finally, the structural association of Phase I and 11 mechanisms will be explored. On the basis of these studies it may ultimately be possible to develop therapeutic strategies for the manipulation of bile acids and other endobiotics in patients with liver disease.
Showing the most recent 10 out of 18 publications
