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 enzy me. However, contrary to an earlier in vivo observation, the present s tudy failed to find evidence of polymorphism of this enzyme activity i n liver preparations of 84 African green (Cercopithecus aethiops) monk eys. The kinetics of dextromethorphan O-demethylation were similar in liver microsomes from African green (n = 21) and Crab eater (Macaca fa scicularis, n = 7) monkeys (K(m) = 1.1 +/- 0.07 and 1.7 +/- 0.27 muM; V(max) = 215 +/- 71.7 and 152 +/- 21.1 nmol/mg/h, respectively). These K(m) values were lower and less variable than those in liver microsom es from 10 human extensive metabolizers (5.3 +/- 2.43 muM). Furthermor e, the V(max) of the reaction in human liver microsomes was significan tly lower (32 +/- 15.7 nmol/mg/h; P < .001). Inhibitor constants (K(i) values) determined in monkey and human liver microsomes were highly c orrelated (r = 0.97), but two high-affinity inhibitors of the human en zyme (quinidine and lobeline) were approximately 40-fold less potent i n monkey livers than in human livers. These data show that the monkey enzyme is functionally homologous, but is not identical to human hepat ic cytochrome P450 2D6. Failure to observe poor metabolizer monkeys do es not preclude their potential usefulness in evaluating the role of h uman hepatic cytochrome P450 2D6 activity in drug addiction and neurot oxicity because of the possibility of producing poor metabolizer pheno copies by potent hepatic cytochrome P450 2D6-like enzyme inhibitors in monkeys.