Dose‐dependent metabolic excretion of bromobenzene and its possible relationship to hepatotoxicity in rats

Abstract

Male Sprague‐Dawley rats received an intraperitoneal injection of 0.25‐, 0.5‐, 1.0‐, 2.5‐, and 5.0‐mmol/kg dose of bromobenzene in corn oil. The metabolic fate of bromo‐benzene was studied by measuring its various urinary metabolites 24 h following bromobenzene administration. The hepatotoxicity of bormobenzene was estimated by determination of the serum glutamic‐oxaloacetic and glutamic‐pyruvic transaminase activities (SGOT and SGPT) 24 h after dosing. Treatment of rats with bromobenzene at up to 0.5 mmol/kg did not influence the transaminase activities, but significant increases in such activities began to manifest at a dose of 1 mmol/kg. However, no further increase in hepatotoxic response was induced on exposure to higher doses (2.5 and 5.0 mmol/kg) of bromobenzene. The urinary excretion of toxic doses of bromobenzene was nonlinear, based on the quantitative composition of various urinary metabolites. Furthermore, the fraction of the dose converted to thioethers, p‐bromophenol, m‐bromophenol, and total phenolic metabolites decreased with increasing toxic dose, suggesting their formation to be capacity‐limited. The ratios of thioethers to total phenolic metabolites, of thioethers to p‐bromophenol, and of thioethers to o‐bromo‐phenol decreased with increasing dose of bromobenzene. The correlation of the dose‐dependent fate of metabolic excretion of bromobenzene with the results of the dose‐hepatotoxic response curves supports the conclusion that there exists an apparent threshold dose (∼1–2.5 mmol/kg) for the toxic effects of bromobenzene that coincides with saturation of the metabolic pathways involving both glutathione/glutathione S‐transferase(s) and formation of certain phenolic derivatives for its detoxification. All these results further suggest a role of a saturable, metabolic activation process involving 3,4‐epoxide rather than 2,3‐epoxide of bromobenzene in the development of its hepatotoxicity.