The objectives of these investigations are to: 1) determine the absolute mechanisms by which halogenated volatile anesthetics produce hepatotoxicity in the two clinically relevant animal models successfully initiated in this laboratory; 2) proceed with ongoing studies of therapeutic agents to ameliorate this toxicity; 3) provide clinical guidelines to reduce the risk of anesthetic hepatotoxicity. Halothane and enflurane, two widely used volatile anesthetics that are known to produce sporadic and spontaneous liver damage, will initially be tested. These agents will be administered to animals under conditions of mild hypoxia or pretreatment with polychlorinated biphenyls, both of which promote the production of toxic metabolites in vivo. A variety of parameters will be tested in the model systems to understand the absolute conditions required for toxicity, such as pretreatment with a variety of agents known to alter biotransformation, various oxygen tensions, species, sex and strain variations, diet, and liver integrity. A multitude of therapeutic agents will be tested in the model systems, including specific biotransformation inhibitors and protective agents. Considerable emphasis will be placed on determining the metabolic pathways for these anesthetics because biotransformation appears to be prerequisite for expression of toxicity. Actual metabolites will be isolated, identified and quantified. Covalent binding of radiolabeled anesthetics to tissue macromolecules will be performed to correlate tissue damage with the production of reactive intermediates. The information from these studies will provide us with clinical guidelines for anesthetic administraiion that will minimize the risk of hepatotoxicity.
