SELECTIVE-INHIBITION OF MAJOR-DRUG METABOLIZING CYTOCHROME-P450 ISOZYMES IN HUMAN LIVER-MICROSOMES BY CARBON-MONOXIDE

The selectivity of carbon monoxide binding to specific human cytochrom e P450 isozymes was investigated by studying its inhibition of prototy pe reactions for 3 major drug metabolizing P450s in liver microsomes: dextromethorphan O-demethylation and (+)-bufuralol 1'-hydroxylation (P 450DB1, CYP2D6), diclofenac 4'-hydroxylation (P450TB, CYP2C subfamily) , and midazolam 1'-hydroxylation (P450NF, CYP3A subfamily). The affini ty of carbon monoxide is different for each P450 isozyme. Warburg part ition coefficients were 0.35, 1.1 and 3.9 mu M for P450DB1, P450TB and P450NF, respectively. Differential inhibition by carbon monoxide may be a useful tool to identify specific human cytochrome P450 isozymes i n the early screening of drug biotransformation catalysts. Further stu dies involving other P450 isozymes and substrates should extend our un derstanding of the phenomena and their implications.