Glutathione and Mercapturic Acid Conjugations in the Metabolism of 2,4-Dinitrobromobenzene

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Abstract
The formation of glutathione (GSH) conjugate in the detoxification of [Ring-UL-14C]-2,4-dinitrobromobenzene (DNBB) was investigated using rat liver cytosolic fraction. The mercapturic acid conjugate in rats was also studied by collection of urine of rats dosed with radioactive DNBB by intraperitoneal injection. The glutathione replaced the labile bromo atom and formed the conjugate, S-(2,4-dinitrophenyl)glutathione. The GSH conjugate was confirmed by amino acid analysis and by mass spectroscopy as well as co-cochromatography with the synthetic compound. The amount of formation of GSH conjugate was dependent on the amount of GSH added in the incubation mixture. When [Ring-UL-14C]-DNBB was dosed to rats, 69% and 17% of the radiocarbon was excreted via the urine and feces within 72 hours, respectively. The major radioactive metabolite present in the acid urine of DNBB treated was S-(2,4-dinitrophenyl)mercapturic acid accounting for 60% of the administered dose of radiocarbon. The mercapturic acid conjugate was identified similarly to methods used for identification of GSH conjugate. The data demonstrated that GSH conjugate, formed initially and then subsequently converted into the mercapturic acid excreted in the urine, was the major metabolic pathway in the metabolism of 2,4-dinitrobromobenzene.