VARYING EFFECTS OF SULFHYDRYL NUCLEOPHILES ON ACETAMINOPHEN OXIDATION AND SULFHYDRYL ADDUCT FORMATION

The effects of glutathione, cysteine, N-acetylcysteine, cysteamine, .alpha.-mercaptopropionylglycine and methionine on the NADPH-dependent metabolism and covalent binding of acetaminophen were examined in mouse liver microsomal incubations. With the exception of methionine, all of the nucleophiles decreased covalent binding by forming adducts with the electrophilic metabolite of acetaminophen. The adducts were quantitatively measured by high pressure liquid chromatography. In contrast to glutathione, N-acetylcysteine and .alpha.-mercaptopropionylglycine, both cysteamine and cysteine in high concentrations also decreased covalent binding of acetaminophen through another mechanism, inhibition of the formation of the reactive acetaminophen metabolite. Both inhibition of metabolite formation and detoxification of metabolite by sulfhydryl adduct formation are mechanisms that may be important in reducing acetaminophen toxicity in overdosed patients treated with these nucleophiles.