Abstract

The mechanism of 3-methylcholanthrene (3-MC)-induced protection from bromobenzene's hepatotoxicity has been investigated. Determination of the metabolic half-life of bromobenzene indicated that 3-MC induction did not alter the rate of metabolism of bromobenzene in vivo. In contrast, phenobarbital and SKF 525A treatments, which enhance and block, respectively, bromobenzene-induced liver necrosis, enhanced and blocked bromobenzene metabolism. Measurement of bromobenzene metabolism in vitro indicated that 3-MC caused a modest induction of metabolism. Thus 3-MC-induced protection, unlike the SKF 525A effect, is not due to an inhibition of bromobenzene metabolism. Determination of the urinary metabolites of bromobenzene indicated that 3-MC induction caused an increased excretion of bromophenyldihydrodiol and bromocatechol. These metabolites arise from epoxide hydrase-catalyzed hydration of bromobenzene epoxide, suggesting that 3-MC protection is due to an increased capacity to detoxify the chemically highly reactive epoxide. In addition, 2-bromophenol was found to be a major urinary metabolite of hromobenzene in 3-MC-induced rats, suggesting that 3-MC induction may also divert bromobenzene metabolism into a comparatively nontoxic pathway.