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 cytochrome P450 isozymes was investigated by studying its inhibition of prototype reactions for 3 major drug metabolizing P450s in liver microsomes: dextromethorphan O-demethylation and (+)-bufuralol 1'-hydroxylation (P450DB1, CYP2D6), diclofenac 4'-hydroxylation (P450TB, CYP2C subfamily), and midazolam 1'-hydroxylation (P450NF, CYP3A subfamily). The affinity of carbon monoxide is different for each P450 isozyme. Warburg partition coefficients were 0.35, 1.1 and 3.9 microM for P450DB1, P450TB and P450NF, respectively. Differential inhibition by carbon monoxide may be a useful tool to identify specific human cytochrome P450 isozymes in the early screening of drug biotransformation catalysts. Further studies involving other P450 isozymes and substrates should extend our understanding of the phenomena and their implications.
Leemann
T
T
Department of Medicine, University Hospital, Geneva, Switzerland.
Bonnabry
P
P
Dayer
P
P
D002248:Carbon Monoxide / Q000378:metabolism / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003915:Dextromethorphan / Q000378:metabolism; D004008:Diclofenac / Q000378:metabolism; D004983:Ethanolamines / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D008874:Midazolam / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010090:Oxidoreductases, O-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism
D065607:Cytochrome P-450 Enzyme Inhibitors; D004983:Ethanolamines; D004008:Diclofenac; D003915:Dextromethorphan; D002248:Carbon Monoxide; C010831:bufuralol; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010090:Oxidoreductases, O-Demethylating; C052861:dextromethorphan O-demethylase; C043872:bufuralol 1'-hydroxylase; D008874:Midazolam