Abstract

Studies of drug toxicity in humans are limited by the paucity of noninvasive approaches for assessing individual susceptibility to toxicity. An in vitro system for examining acetaminophen toxicity has been developed by using human lymphocytes and a mouse microsomal drug metabolizing system. Acetaminophen metabolites produced by the microsomes caused a dose-dependent depletion of lymphocyte glutathione content. No depletion was seen with heat-inactivated microsomes or in the absence of the metabolizing system. Toxicity to the lymphocytes was assayed by trypan blue dye exclusion, release of lactic dehydrogenase to the culture medium and loss of ability to respond to concanavalin A with [3H]thymidine incorporation into deoxyribonucleic acid. Toxicity was marked at concentrations of acetaminophen causing greater than 80% depletion of glutathione, similar to plasma concentrations associated with hepatotoxicity in vivo. The method may serve as a means of examining individual differences in cell defenses against electrophilic drug metabolite toxicity.