Antagonism of chlorobenzene-induced hepatotoxicity by lindane

In two complete replicates of a 2 × 2-fractorial-designed experiment involving chlorobenzene and γ-hexachlorocyclohexane (lindane), the hepatotoxicity induced by a challenge dose of chlorobenzene was altered by the pretreatments due to selective changes in various metabolis pathways. Pretreatment with either toxicant, alone or in combination, elevated the relative metabolism of 1.12 g chlorobenzene/kg to conjugated and polar metabolites. The relative importance of these pathways was increased most by pretreatment with chlorobenzene + lindane and least with chlorobenzene. The incidence and severity of chlorobenzene-induced hepatocellular necrosis was dependent on how much the pretreatments increased excretion of these metabolites relative to that of p-chlorophenol, since the conjugates and polar metabolites represent an inactivation of the toxic chlorobenzene-3,4-epoxide whereas p-chlorophenol reflects its formation. Thus these changes in the metabolic pathways resulted in either (i) a marginally significant decrease in hepatotoxicity (chlorobenzene pretreatment); (ii) significant reduction in both the incidence and severity of the lesions (lindane pretreatment); or (iii) absence of centrilobular hepatocellular necrosis in all but 1 of 12 rats where a minimal degree of necrosis was present (chlorobenzene + lindane pretreatment). In this study, the effect of pretreatment with xenobiotics on chlorobenzene-induced hepatotoxicity was dependent on how much the pretreatments altered the inactivation of chlorobenzene-3,4-epoxide relative to its formation.