A comparison of basal and induced hepatic microsomal cytochrome P450 monooxygenase activities in the cynomolgus monkey (Macaca fascicularis) and man.
1. The specific activities of hepatic microsomal cortisol 6beta-hydroxylase, coumarin 7-hydroxylase, S-mephenytoin 4'-hydroxylase and phenoxazone hydroxylase and the O-dealkylations of seven homologous alkoxyresorufins were < 3-fold different between the untreated (UT) cynomolgus monkey and man. 2. Heptoxy- and octoxyresorufin O-dealkylase, S-mephenytoin N-demethylase and dextromethorphan O-demethylase specific activities were > 6-fold higher, whereas tolbutamide hydroxylase was almost 5-fold lower in the UT monkey than in man. 3. Phenobarbitone induced (2-6-fold) coumarin 7-hydroxylase, cortisol 6beta-hydroxylase, S-mephenytoin N-demethylase, phenoxazone hydroxylase and benzyloxyresorufin O-dealkylase activities, but not the O-dealkylations of pentoxyresorufin or other alkoxyresorufins, in monkey. 4. Rifampicin induced (2-3-fold) cortisol 6beta-hydroxylase, S-mephenytoin 4'-hydroxylase, S-mephenytoin N-demethylase and tolbutamide hydroxylase activities, the O-dealkylations of methoxy-, ethoxy- and propoxyresorufin and CYP2C- and CYP3A-immunorelated proteins in monkey. 5. Dextromethorphan O-demethylase was significantly reduced by both phenobarbitone and rifampicin treatment in monkey. 6. Beta-naphthoflavone induced (8-39-fold) the O-dealkylations of several alkoxyresorufins, the greatest effect being on propoxyresorufin, but had no effect on the other activities measured in monkey. 7. Constitutive hepatic microsomal CYP2D6-immunorelated proteins were expressed at apparently much higher levels in monkey than in man.
Weaver
R J
RJ
Servier Research & Development, Fulmer, Slough, UK.
Dickins
M
M
Burke
M D
MD
D000328:Adult; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D015151:Immunoblotting; D008252:Macaca fascicularis; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D008875:Middle Aged; D010634:Phenobarbital / Q000494:pharmacology; D012293:Rifampin / Q000494:pharmacology; D013250:Steroid Hydroxylases / Q000187:drug effects / Q000378:metabolism*; D019324:beta-Naphthoflavone / Q000494:pharmacology
D004791:Enzyme Inhibitors; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D012293:Rifampin; D010634:Phenobarbital