A variety of organic sulfides have been found to inhibit the toxicity or carcinogenicity of environmental chemicals. The investigators' previous studies indicate that rat hepatic cytochrome P450IIE1, an enzyme that activates low molecular weight organic compounds, is inhibited and inactivated by diallyl sulfide (DAS), a dietary chemical, and disulfiram (DSF), a drug used in avoidance therapy for alcohol abuse. The long-term goal of this project is to understand the biological action of this type of organic sulfide and to explore their usefulness in the prevention of chemical toxicity and carcinogenesis. The present proposal seeks to: further characterize the effects of DAS and DSF administration, both chronic and acute, on P450s and other enzymes in the liver and other tissues by specific enzyme assays and immunoquantitation; elucidate the molecular mechanisms of inhibition and inactivation of P450IIE1 by DAS and DSF in vivo and in vitro; delineate the effects of organic sulfides on the metabolism and toxicity of selected xenobiotics; explore the possible use of organic sulfides for the prevention of chemical toxicity; characterize other biological effects of organic sulfides; and evaluate the relevance of dietary levels of organic sulfides to the protection against chemical toxicity. P450IIE1 plays a vital role in catalyzing the activation of many environmental toxicants and carcinogens. The proposed studies on the inactivation of this enzyme by organic sulfides may form the basis for the prevention of toxicity and carcinogenesis by this type of compound either derived from the diet or taken as prophylactically.
