Species variation in the bioactivation of tacrine by hepatic microsomes

Xenobiotica. 1995 Jan;25(1):103-16. doi: 10.3109/00498259509061837.


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.

Publication types

  • Comparative Study

MeSH terms

  • Amino Acids / pharmacology
  • Animals
  • Biotransformation
  • Cholinesterase Inhibitors / metabolism*
  • Chromatography, High Pressure Liquid
  • Cricetinae
  • Dogs
  • Humans
  • Hydroxylation / drug effects
  • Mass Spectrometry
  • Mice
  • Microsomes, Liver / metabolism*
  • NADP / metabolism
  • Protein Binding
  • Rabbits
  • Rats
  • Species Specificity
  • Sulfhydryl Compounds / pharmacology
  • Tacrine / metabolism*


  • Amino Acids
  • Cholinesterase Inhibitors
  • Sulfhydryl Compounds
  • Tacrine
  • NADP