MECHANISM OF ACETAMINOPHEN HEPATOTOXICITY

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Acetaminophen (APAP) is a widely used, safe, antipyretic analgesic which, when taken in excess doses, causes seveere hepatic necrosis. Hepatoxicity has been shown to be the result of microsomal activation of APAP to an electrophile which first depletes glutathione (GSH) reserves and then binds covalently to critical cell components. The proposed research is aimed at elucidating the mechnism(s) hwereby APAP causes cell death. The following specific questions will be addressed: 1) How is covalent binding to different subcellular organelles related to the development of the hepatotoxicity? 2) How is APAP alteration of organelle structure and function related to the hepatotoxocity? 3) Can the toxic process leading to APAP toxicity be modulated after covalent binding has occurred? 4) Does GSH have an additional protective role against APAP hepatotoxicity after miximal covalent binding has occurred? 5) What is the role of lipid peroxidation in subcellular organelles in the development of APAP-induced hepatotoxicity? The approach will involve determining the sequence of biochemical and morphological alterations which occur in hepatocytes subsequent to exposure to a hepatotoxic concentration of APAP. Specifically, we will study the dose and time response profile of APAP electrophile covalent binding to specific organelles and compare this with APAP effects upon organelle structure and function as well as correlate such effects to the acute hepatotoxic effects of APAP. Special attention will be given to elucidation of the effects of APAP on plasma membrane structure and function. In addition, lipid peroxidation will be measured in specific organelles and, glutathione depletion or enhancement will be employed in attempts to modulate toxicity while monitoring selected parameters from the dose and time studies. The proposed research will elucidate the events which occur during APAP poisoning and will permit the development of rational alternative therapies for the prevention of severe hepatotoxicity after exposure to normally hepatoxic doses of APAP and other hepatotoxins.