Effects of chronic acetone administration on ethanol-inducible monooxygenase activities in the rat

Abstract

Liver microsomal monooxygenase activities known to be ethanol-inducible were determined in female Sprague-Dawley rats after 2-week treatment with 1% (v/v) acetone. Daily acetone intake was in the order of 1.2 g/kg. The final body weight, liver weight and microsomal protein content of acetone-treated rats were identical to those of untreated controls. Microsomal NADPH-cytochrome c reductase activity was also unaffected, while cytochrome P-450 content was only increased 12-18%. Ethanol-inducible p-nitrophenol hydroxylation, aniline hydroxylation and 7-ethoxycoumarin O-deethylation activities were enhanced 5.3-, 4.4- and 2.6-fold, respectively, by chronic acetone treatment. The sex-dependent inducing effect of ethanol on benzphetamine N-demethylation activity in female rats was not observed however, after acetone. Addition of acetone in vitro had a stimulatory effect on aniline hydroxylation by microsomes from control and acetone-induced rats. Acetone, however, was found to be a competitive inhibitor of p-nitrophenol hydroxylation activity (apparent Ki = 1.8 mM), an observation suggesting that p-nitrophenol is a more selective substrate than aniline for rat liver ethanol- and acetone-inducible cytochrome P-450j. Interruption of the chronic acetone treatment for 24 hr resulted in the almost complete disappearance of its inducing affects, this treatment apparently reproducing only the rapidly reversible preferential inducing effects of chronic ethanol administration. This experimental model of induction by acetone in the rat, when compared to chronic ethanol administration, would thus permit a more selective look at the consequences of these common inducing effects in particular, with respect to drug metabolism and toxicity in vivo, and this, in the absence of the hepatotoxic effects of ethanol itself.