Metabolic activation and detoxification of bromobenzene leading to cytotoxicity

Two hepatic microsomal metabolic pathways of bromobenzene, o-bromophenol (via a nontoxic 2,3-epoxide) and p-bromophenol (via a toxic 3,4-epoxide) were studied in C57BL/J and Balb/cJ mice. A significant quantitative difference was found; in particular, the constitutive activity of the toxic 3,4-epoxide pathway. The specific activity in BALB/cJ mice was 93.4 nmol/min/100 mg of protein compared to 47.5 nmol/min/100 mg of protein in the C57BL/J mice. In contrast, no significant difference was found in the 2,3-epoxide pathway in either strain. In addition, the major detoxifying pathways of the epoxides; e.g. microsomal epoxide hydrase and cytoplasmic glutathione transferase were determined in the BALB/cJ and C57BL/J mice and no significant differences in these activities were found. Furthermore, there were no significant differences in the quantity of the dihydrodiol or mercapturic acid products in the two strains of mice. A comparative investigation of hepatic centrolobular necrosis and pharmacodynamic blood profile after bromobenzene administration was undertaken in these mice. Extensive hepatic necrosis occurred in 90% of the BALB/cJ mice, whereas 80% of C57BL/J mice had no pathological changes. Furthermore, the rate of disappearance of bromobenzene in blood of individual mice indicated a half-life of 28 ± 5.3 min for BALB/cJ and 60 ± 6.4 min for C57BL/J mice. This study furnishes excellent correlation between in vivo hepatic necrosis, rate of disappearence of bromobenzene in blood and in vitro enzymatic formation of p-bromophenol via 3,4-epoxidation.