The possible role of the ethanol-inducible isozyme of cytochrome P450 in the metabolism and distribution of carbon disulfide.

Acute treatment with ethanol and other alcohols has been shown to potentiate the hepatotoxicity of certain xenobiotics, in part via induction of the mixed-function oxidase (MFO) system. Carbon disulfide (CS2)-induced hepatotoxicity and inhibition of the MFO system have been shown to be a consequence of MFO metabolism. In the present study, the ability of several different alcohols to induce the hepatic MFO metabolism of CS2 and the effects of this induction on CS2 distribution and hepatotoxicity were examined in rats. Eighteen hours after alcohol administration (1/2 LD50 dose, po), CS2 microsomal MFO metabolism was significantly enhanced, in order of descending potency, by isopropanol, methanol, and ethanol pretreatments, but not by isobutanol pretreatment. The degree of enhancement of CS2 metabolism by different alcohols paralleled the enhancement of nitroanisole O-demethylation and aniline hydroxylation, MFO activities associated with the ethanol-inducible isozyme of cytochrome P450. CS2 (1 mg/kg, ip, 3 hr) inhibited only the cytochrome P450-mediated activities enhanced by alcohol pretreatment. These results suggest that CS2 metabolism is catalyzed by the ethanol-inducible isozyme. Alcohol-induced rats had significantly more 14CS2-derived radioactivity in the liver than control and isobutanol-pretreated rats 3 hr after dosing (1 mg/kg, ip). However, only methanol pretreatment resulted in an increased retention of 14CS2-derived radioactivity in plasma, brain, and kidney. Unlike other alcohol pretreatments, methanol decreased the total 14C expired during the 3-hr period after CS2 dosing and caused a significant (twofold) increase in plasma glutamic-pyruvic transaminase, measured 24 hr after CS2 exposure (625 mg/kg). These data indicate that alcohol induction of MFO-dependent CS2 metabolism per se is not sufficient to result in CS2-induced hepatic damage although it does lead to loss of specific cytochrome P450 function.