Human hepatic cytochrome P450 2D6-like activity in nonhuman primates: catalytic characterization in vitro.
Previous studies have identified the monkey as an animal model for the genetic polymorphism affecting human hepatic cytochrome P450 2D6 enzyme. However, contrary to an earlier in vivo observation, the present study failed to find evidence of polymorphism of this enzyme activity in liver preparations of 84 African green (Cercopithecus aethiops) monkeys. The kinetics of dextromethorphan O-demethylation were similar in liver microsomes from African green (n = 21) and Crab eater (Macaca fascicularis, n = 7) monkeys (Km = 1.1 +/- 0.07 and 1.7 +/- 0.27 microM; Vmax = 215 +/- 71.7 and 152 +/- 21.1 nmol/mg/h, respectively). These Km values were lower and less variable than those in liver microsomes from 10 human extensive metabolizers (5.3 +/- 2.43 microM). Furthermore, the Vmax of the reaction in human liver microsomes was significantly lower (32 +/- 15.7 nmol/mg/h; P < .001). Inhibitor constants (Ki values) determined in monkey and human liver microsomes were highly correlated (r = 0.97), but two high-affinity inhibitors of the human enzyme (quinidine and lobeline) were approximately 40-fold less potent in monkey livers than in human livers. These data show that the monkey enzyme is functionally homologous, but is not identical to human hepatic cytochrome P450 2D6. Failure to observe poor metabolizer monkeys does not preclude their potential usefulness in evaluating the role of human hepatic cytochrome P450 2D6 activity in drug addiction and neurotoxicity because of the possibility of producing poor metabolizer phenocopies by potent hepatic cytochrome P450 2D6-like enzyme inhibitors in monkeys.
Wu
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Clinical Research and Treatment Institute of the Addiction Research Foundation, University of Toronto, Ontario, Canada.
Otton
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SV
Morrow
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Inaba
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Kalow
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Sellers
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EM
D000818:Animals; D002522:Chlorocebus aethiops; D019389:Cytochrome P-450 CYP2D6; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6