Affinity of drugs for cytochrome P-450 determined by inhibition of p-nitrophenetole O-deethylation by rat liver microsomes.
The rate of conversion of p-nitrophenetole to p-nitrophenol by rat liver microsomes was studied. Inhibition of the reaction by CO and by SKF 525A and the absolute dependence on NADPH and oxygen indicate that cytochrome P-450 catalyzes the reaction. The apparent Km for oxygen was 0.07 microM. Furthermore, cytochrome b5 seemed to be involved in the formation of p-nitrophenol. The effect on p-nitrophenol formation of drugs known to be involved in drug interaction in clinical practice was studied. There was a competitive inhibition by phenytoin (inhibitor constant, Ki, 30 microM), disulfiram (Ki, 2 microM) and chloramphenicol (Ki, 20 microM), whereas a mixed-type inhibition by isoniazid was observed (Ki, 1,3 mM and Kii, 10,6 mM).
D000818:Animals; D001711:Biotransformation; D002248:Carbon Monoxide / Q000494:pharmacology; D002701:Chloramphenicol / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004221:Disulfiram / Q000494:pharmacology; D004347:Drug Interactions; D007538:Isoniazid / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D009578:Nitrobenzenes / Q000378:metabolism*; D009596:Nitrophenols / Q000378:metabolism; D010084:Oxidation-Reduction; D010672:Phenytoin / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D009578:Nitrobenzenes; D009596:Nitrophenols; D010672:Phenytoin; D002701:Chloramphenicol; D002248:Carbon Monoxide; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; C013154:4-nitrophenetol; D004221:Disulfiram; D007538:Isoniazid; C024836:4-nitrophenol