TACRINE TRANSAMINITIS - POTENTIAL MECHANISMS

The potential role of oxidative metabolism in tacrine (1,2,3,4-tetrahy dro-9-amino acridine)-induced transaminitis has been investigated in a n in vitro system. In the presence of human or rat liver microsomes, t acrine undergoes nicotinamide adenine dinucleotide phosphate-dependent metabolism to stable, protein-reactive, cytotoxic metabolites. In hum an liver microsomes, CYP1A was identified as the major enzyme involved in the metabolism and bioactivation of tacrine. The reactive metaboti te formed is an electrophilic species that may interact with cellular thiols, such as protein and reduced glutathione. Reactive metabolite f ormation 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 i nteraction of quinone methide with essential cellular macromolecules o r from induction of futile redox cycling within the cell, brought abou t 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.