Isopropanol and acetone potentiation of carbon tetrachloride‐induced hepatotoxic1ty: Single versus repetitive pretreatments in rats

Abstract

Acute oral pretreatment of rats with isopropanol or acetone results in a dose-related potentiation of CCl4 hepatotoxicity. Minimally effective doses (MED) and noneffective doses (NED) of both agents were estimated to be 0.25 and 0.10 ml/kg, respectively. Six MED given twice a day over 3 d caused a greater potentiation than a single MED, but not as much as that produced by the total dose given singly. Six NED given over 3 d did not potentiate CCl4, whereas the total dose did when given singly. A threshold for isopropanol and acetone appears to exist in the rat. A total dose of 1.5 ml/kg acetone was administered by four different treatment regimens (bolus, divided doses, infusion) over 3 d. Potentiation of CCl4 hepatotoxicity was then correlated with blood pharmacokinetic parameters: area under the concentration-time curve and peak blood concentration. An excellent correlation was found between the degree of potentiation observed and the peak blood concentration attained, but no correlation was found with area under the curve. Results of iv acetone infusions (over 3 d) with higher doses support the hypothesis that a threshold concentration of acetone is critical in the potentiation of CCl4 hepatotoxicity in the rat.