title: Species variation in the bioactivation of tacrine by hepatic microsomes.
abstract: 1. The metabolite profile of tacrine (1,2,3,4-tetrahydro-9-amino acridine) was similar in hepatic microsomes from man, rat, dog, rabbit, mouse and hamster. Major metabolites were 1-, 2-, 4- and 7-OH tacrine. Only 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 undergo significantly less bioactivation than either 7-OH tacrine or tacrine itself. 4. In the presence of hepatic microsomes and thiol-containing agents protein-reactive metabolite formation was significantly reduced. With mercaptoethanol present a stable thioether adduct was generated from both tacrine and 7-OH tacrine. 5. Analysis of the thioether adduct by mass spectrometry yielded a molecular ion of m/z 290 consistent 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 tacrine involving an initial 7-hydroxylation followed by a postulated 2-electron oxidation to yield a reactive quinone methide. This mechanism of bioactivation appears to be identical in human and animal hepatic microsomes.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Liverpool, UK.
authors.forename: S
authors.initials: S
authors.lastname: Madden
authors.forename: V
authors.initials: V
authors.lastname: Spaldin
authors.forename: R N
authors.initials: RN
authors.lastname: Hayes
authors.forename: T F
authors.initials: TF
authors.lastname: Woolf
authors.forename: W F
authors.initials: WF
authors.lastname: Pool
authors.forename: B K
authors.initials: BK
authors.lastname: Park
mesh_terms: D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D001711:Biotransformation; D002800:Cholinesterase Inhibitors / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D004285:Dogs; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D013058:Mass Spectrometry; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D011485:Protein Binding; D011817:Rabbits; D051381:Rats; D013045:Species Specificity; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D013619:Tacrine / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D002800:Cholinesterase Inhibitors; D013438:Sulfhydryl Compounds; D013619:Tacrine; D009249:NADP