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 (CS 2)-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 CS 2 and the effects of this induction on CS 2 distribution and hepatotoxicity were examined in rats. Eighteen hours after alcohol administration ( 1 2 LD50 dose, po), CS 2 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 CS 2 metabolism by different alcohols paralleled the enhancement of nitroanisole O-demethylation and aniline hydroxylation, MFO activities associated with the ethanol-inducible isozyme of cytochrome P 450. CS 2 (1 mg/kg, ip, 3 hr) inhibited only the cytochrome P 450-mediated activities enhanced by alcohol pretreatment. These results suggest that CS 2 metabolism is catalyzed by the ethanol-inducible isozyme. Alcohol-induced rats had significantly more 14CS 2-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 14CS 2-derived radioactivity in plasma, brain, and kidney. Unlike other alcohol pretreatments, methanol decreased the total 14C expired during the 3-hr period after CS 2 dosing and caused a significant (twofold) increase in plasma glutamic-pyruvic transaminase, measured 24 hr after CS 2 exposure (625 mg/kg). These data indicate that alcohol induction of MFO-dependent CS 2 metabolism per se is not sufficient to result in CS 2-induced hepatic damage although it does lead to loss of specific cytochrome P 450 function.