Inhibition of rat liver monooxygenase activities by 2-methyl-1,4-naphthoquinone (menadione).
In rat liver microsomes, 2-methyl-1,4-naphthoquinone (menadione) inhibits cytochrome P450 (cyt P450)-mediated aniline-p-hydroxylation and aminopyrine-N-demethylation with Ki values of 12 and 14.5 microM, respectively. The inhibitions of aniline-p-hydroxylation and aminopyrine-N-demethylation are mixed uncompetitive-noncompetitive and mixed competitive-noncompetitive, respectively. NADP antagonizes the inhibitory effect of menadione on aniline-p-hydroxylase activity but not that on aminopyrine-N-demethylase activity. Menadione does not give rise to any spectral change of cyt P450, but modifies the type I binding spectrum induced by aminopyrine. In contrast, menadione does not change the type II binding spectrum induced by aniline. These results indicate that menadione may inhibit aniline-p-hydroxylase activity by acting as a substrate for NADPH-cyt P450 reductase in the place of cyt P450 and inhibit aminopyrine-N-demethylase activity by impairing the binding of aminopyrine to cyt P450.
Floreani
M
M
Department of Pharmacology, University of Padova, Italy.
Carpenedo
F
F
D000633:Aminopyrine N-Demethylase / Q000037:antagonists & inhibitors*; D000815:Aniline Hydroxylase / Q000037:antagonists & inhibitors*; D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D013053:Spectrophotometry; D014812:Vitamin K / Q000494:pharmacology*
D065607:Cytochrome P-450 Enzyme Inhibitors; D014812:Vitamin K; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D000815:Aniline Hydroxylase; D000633:Aminopyrine N-Demethylase