Oltipraz, a dithiolthione, has been shown to ameliorate the toxicity of several hepatotoxins and tumor development of several carcinogens. Our preliminary studies indicate that oltipraz can prevent the hepatotoxicity associated with acetaminophen and allyl alcohol. The objective of this proposal is to examine the ability of oltipraz in preventing the hepatotoxicity of acetaminophen in hamsters and to explore possible mechanisms for the protective action. Initial studies are designed to establish the effectiveness of oltipraz, when administered in an acute manner, as well as by a dietary route, in preventing the hepatotoxicity induced by acetaminophen. Mechanism studies will be directed to examine oltipraz induced alterations in acetaminophen pharmacokinetics, urinary metabolite profile, and in vivo covalent binding. Hepatocytes will be used to determine if oltipraz alters the rate and/or route of phase I and II biotransformation of acetaminophen. The hypothesis to be tested is that oltipraz exerts its protective effect by altering acetaminophen biotransformation, and thus, interferes with the generation of the reactive metabolite. We will also test a second hypothesis that oltipraz alters the cellular levels and/or availability of glutathione, the tripeptide intimately involved in the hepatotoxicity of acetaminophen. The effect of oltipraz on the levels of glutathione as well as the attendant enzymes for its synthesis and utilization will be assessed. The results of these studies will provide useful information on the mechanisms(s) by which oltipraz protects against chemically induced hepatotoxicity.
