The potential role of oxidative metabolism in tacrine (1,2,3,4-tetrahydro-9-amino acridine)-induced transaminitis has been investigated in an in vitro system. In the presence of human or rat liver microsomes, tacrine undergoes nicotinamide adenine dinucleotide phosphate-dependent metabolism to stable, protein-reactive, cytotoxic metabolites. In human liver microsomes, CYP1A was identified as the major enzyme involved in the metabolism and bioactivation of tacrine. The reactive metabolite formed is an electrophilic species that may interact with cellular thiols, such as protein and reduced glutathione. Reactive metabolite formation is a two-step process involving an initial 7-hydroxylation of tacrine, followed by a postulated 2-electron oxidation that yields a chemically reactive quinone methide. Cell damage may result from the interaction of quinone methide with essential cellular macromolecules or from induction of futile redox cycling within the cell, brought about by induction of lipid peroxidation, generation of free radicals, and depletion of cellular cofactors such as glutathione. The presence of these processes in vivo may lead to a toxic reaction dependent on the balance between drug bioactivation and drug detoxication.