Conversion of bromobenzene to 3-bromophenol. A route to 3- and 4-bromophenol through sulfur-series intermediates derived from the 3,4-oxide.

Premercapturic acids derived from bromobenzene 3,4-oxide were found to act as precursors of 3- and 4-bromophenol in the rat and guinea pig. The 4-S- and 3-S- positional isomers used in this study were rat urinary metabolites and were prepared in unlabeled, radioactive, and 2,4,6-d3-labeled forms. These are not guinea pig urinary metabolites; the guinea pig does not completely acetylate cysteine conjugates, and this effect leads to urinary products arising from deamination of the cysteine moiety rather than to urinary premercapturic acids. Conversion to phenols was found to be much greater in the guinea pig than in the rat. We interpret our results as indicating that cysteine adducts, rather than the N-acetylcysteine adducts which were administered, are required intermediates in this metabolic route to 3- and 4-bromophenol. This route to phenols may be the major mode of phenol formation for many aromatic compounds. Sulfur-series metabolic products from bromobenzene also include thiocatechols, and these metabolites may be responsible for the hepatotoxicity of bromobenzene in high dosage.

Bromobenzene metabolism in the rat and guinea pig.

The metabolism of bromobenzene was studied in the rat and guinea pig with respect to three considerations: the dose and species dependence of 3-bromophenol excretion; the formation of methylthio analogs of dihydrodiols and catechols; and the identification of acidic bivalent sulfur metabolites. In the guinea pig, 3-bromophenol was the major monohydric phenolic metabolite under conditions of both relatively low and relatively high dosage. In the rat, 3-bromophenol and 4-bromophenol were formed in approximately equal amounts. 2-Bromophenol was a minor metabolite in both species. Methylthio analogs of dihydrodiols were found as guinea pig, but not rat, metabolites. Two di(methylthio)dihydroxytetrahydrobromobenzene metabolites were excreted by the rat but not by the guinea pig. These methylthio compounds have not been reported in earlier studies of bromobenzene metabolism. In the guinea pig, the acidic urinary metabolites were a mercaptoacetate, a mercaptolactate, and a mercapturate. In the rat, the acidic metabolites were a mercapturic acid and premercapturic acids. This species difference in urinary acids indicates a difference in acetylation/deacetylation processes for cysteine conjugates.