N-acetylated cysteine conjugates (premercapturic acids) of bromobenzene 3,4-oxide were found to act as precursors of 3- and 4-bromophenol in the rat and guinea pig. The formation of phenols through this pathway is species dependent. The guinea pig shows a higher conversion than the rat and this difference could be due to the degree of acetylate/deacetylate process of cysteine conjugates. This route to phenols may be the major mode of phenol formation for many aromatic compounds whose metabolism involve the reaction of oxides with glutathione. This pathway may be responsible for bromobenzene toxicity in high dosage. The toxicity could be due to the formation of hydrogen sulfide, or to the formation of thiocatechols and/or thioquinones.
The specific aims of this proposed studies are: 1. To study the generality of this sulfur-conjugate pathway to the formation of phenols. Several types of aromatic compounds will be tested. The premercapturic acids will be biosynthesized and purified. Each will be administered to the guinia pig and rat, and the formation of phenols by this pathway will be examined. 2. To define the sequence of reactions and emphasis will be placed on the identification of the direct intermediate for the formation of 3- and 4-bromophenol. The 4-S- and 3-S-cysteine and mercaptopyruvate conjugates and the methylthiohydroxydihydro metabolites of bromobenzene will be synthesized. Each will be tested both in vivo an in vitro for the formation of 3- and 4-bromophenol and the mechanism of sulfur elimination will be studied. 3. To determine the role of acetylation in phenol formation. Synthetic 4-S- and 3-S-cysteine conjugates of bromobenzene will be administered to three differences strain of mice (A/J, C57BL/6J, Swiss Webster). The affect of fast and slow acetylation to the formation of 3- and 4-bromophenol will be examined. 4. The toxicity of the reactive intermediates which could be formed in this sulfur-conjugate pathway to phenols will be studied. Synthetic 4-S- and 3-S-cysteine and mercaptopyruvate conjugate of bromobenzene will be administered to guinea pig, rat and mice, and the liver and kidney toxicity will be examined.
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