SPECIES VARIATION IN THE BIOACTIVATION OF TACRINE BY HEPATIC MICROSOMES

1. The metabolite profile of tacrine (1,2,3,4-tetrahydro-9-amino acrid ine) was similar in hepatic microsomes from man, rat, dog, rabbit, mou se and hamster. Major metabolites were 1-, 2-, 4- and 7-OH tacrine. On ly quantitative differences in metabolite profile were evident between species. 2. Bioactivation to protein-reactive metabolite(s) was seen in microsomes from all species. 3. 7-Methyl tacrine was found to under go significantly less bioactivation than either 7-OH tacrine or tacrin e itself. 4. In the presence of hepatic microsomes and thiol-containin g agents protein-reactive metabolite formation was significantly reduc ed. With mercaptoethanol present a stable thioether adduct was generat ed from both tacrine and 7-OH tacrine. 5. Analysis of the thioether ad duct by mass spectrometry yielded a molecular ion of mit 290 consisten t with the presence of a covalent adduct of 7-OH tacrine complexed in a 1:1 molar ratio with mercaptoethanol. 6. We have therefore provided further evidence for a two-step mechanism in the bioactivation of tacr ine involving an initial 7-hydroxylation followed by a postulated 2-el ectron oxidation to yield a reactive quinone methide. This mechanism o f bioactivation appears to be identical in human and animal hepatic mi crosomes.