Multiple drug metabolism: p-nitroanisole reversal of acetone enhanced aniline hydroxylation.
The unique effect of acetone on the p-hydroxylation of aniline was evaluated in microsomes prepared from control, phenobarbital- and 3-methylcholanthrene-pretreated animals. The existence of multiple forms of the hydroxylase was evaluated as an explanation of the acetone enhancement. Simultaneous metabolism of aniline in the presence of either p-nitroanisole (pNA) or ethylmorphine (EM) was evaluated to probe the participation of different mixed function oxidase systems. Aniline inhibited both N- and O-demethylation, while pNA and EM both inhibited p-hydroxylation of aniline. Acetone decreased the individual  demethylation reactions, but enhanced aniline hydroxylation. In multiple drug reactions, acetone decreased N-demethylation and proportionately increased aniline p-hydroxylation. On the other hand, p-nitroanisole blocked the acetone enhancement of aniline metabolism. Kinetic evaluation of the acetone and p-nitroanisole effects on aniline metabolism indicated that each agent increased the apparent Km' by 4- to 5-fold for aniline in the hydroxylation reaction, but only acetone increased the Vmax'. From the Eadie-Scatchard analysis of the rates of aniline hydroxylation, acetone appeared to produce a biphasic increase in the hydroxylation above 0.75 mM aniline, even in the presence of pNA. Thus, multiple forms of the aniline p-hydroxylase are indicated by their altered activities in the presence of other drugs, and acetone seemed to specifically alter a species having a higher Km' for aniline.
D000096:Acetone / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000814:Aniline Compounds / Q000378:metabolism*; D000815:Aniline Hydroxylase / Q000378:metabolism; D000818:Animals; D000840:Anisoles / Q000494:pharmacology*; D006900:Hydroxylation; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D000814:Aniline Compounds; D000840:Anisoles; D000096:Acetone; D000815:Aniline Hydroxylase; C005306:4-nitroanisole; C023650:aniline