Identification of 2-bromohydroquinone as a metabolite of bromobenzene and o-bromophenol: implications for bromobenzene-induced nephrotoxicity.

2-Bromohydroquinone was identified as a metabolite of both bromobenzene and o-bromophenol in the rat in vivo and in vitro. Identification was based on high-pressure liquid chromatography and gas chromatography-mass spectrometry. Formation of 2-bromohydroquinone by rat liver microsomes from both bromobenzene and o-bromophenol was increased by treatment of rats with either phenobarbital or 3-methylcholanthrene. Covalent binding of o-bromophenol to rat liver microsomes was inhibited by glutathione and ascorbate but not by superoxide dismutase or catalase. Liver microsomes converted o-bromophenol to 2-bromohydroquinone and covalently bound material, whereas kidney and lung microsomes metabolized o-bromophenol less rapidly. Administration of 2-bromohydroquinone to rats caused a dose- and time-dependent decrease in hepatic and renal glutathione levels, an increase in blood urea nitrogen levels and histopathological changes in kidney without causing any alterations to the liver. The histological changes in the kidney were indistinguishable from those observed after either bromobenzene or o-bromophenol administration. However, the dose of 2-bromohydroquinone required to elicit a similar nephrotoxicity was less than 10% of that of bromobenzene. Thus, 2-bromohydroquinone may play a role in the nephrotoxicity observed after bromobenzene administration. Although the nature of the nephrotoxic metabolite of 2-bromohydroquinone is not known, our present results suggest that 2-bromohydroquinone or a conjugate thereof may be formed in the liver and transported to the kidney where it elicits toxicity.