Species variation in the bioactivation of tacrine by hepatic microsomes.
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.
Madden
S
S
Department of Pharmacology and Therapeutics, University of Liverpool, UK.
Spaldin
V
V
Hayes
R N
RN
Woolf
T F
TF
Pool
W F
WF
Park
B K
BK
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*
D000596:Amino Acids; D002800:Cholinesterase Inhibitors; D013438:Sulfhydryl Compounds; D013619:Tacrine; D009249:NADP