Effect of aromatic nitro compounds on oxidative metabolism by cytochrome P-450 dependent enzymes.
The effect of aromatic nitro compounds on the oxidative metabolism of representative type I (hexobarbital and aminopyrene) and type II (aniline and zoxazolamine) substrates by cytochrome P-450 dependent liver enzymes was studied. Nitro compounds (nitrobenzene, p-nitrobenzoate, 2-nitrofluorene, and 2-nitronaphthalene) inhibited the oxidation of type II substrates by rabbit liver microsomal enzymes; however, they had no effect on the metabolism of the type I compounds. Inhibition of type II metabolism was characterized graphically as S,I-hyperbolic non-competitive. The influence of aromatic nitro compounds on the interaction of type I and type II substrates with oxidized and reduced cytochrome P-450 was studied by difference spectroscopy. From Lineweaver-Burke plots, nitro compounds were shown to competitively interact with type II compounds for cytochrome p-450 binding sites. Nitro compounds completely prevented the appearance of a type I binding spectrum with either hexobarbital or aminopyrene even when the modifier was present at concentrations less than 10(-8)M. Aromatic nitro compounds appear to therefore inhibit the metabolism of the type II substrates through a mixed mechanism of interaction with the microsomal drug-metabolizing enzymes.
D000632:Aminopyrine / Q000378:metabolism / Q000494:pharmacology; D000814:Aniline Compounds / Q000378:metabolism / Q000494:pharmacology; D000815:Aniline Hydroxylase / Q000378:metabolism; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004734:Energy Metabolism / Q000187:drug effects*; D006591:Hexobarbital / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009574:Nitro Compounds / Q000378:metabolism / Q000494:pharmacology*; D010084:Oxidation-Reduction; D011817:Rabbits; D015049:Zoxazolamine / Q000378:metabolism / Q000494:pharmacology
D000814:Aniline Compounds; D009574:Nitro Compounds; D000632:Aminopyrine; D003577:Cytochrome P-450 Enzyme System; D015049:Zoxazolamine; D006591:Hexobarbital; D006899:Mixed Function Oxygenases; D000815:Aniline Hydroxylase