Abstract
Bromobenzene is metabolized via the hepatic mixed-function oxygenase system to reactive intermediates; i.e., 2,3- and 3,4-bromobenzene epoxides. These metabolites presumably bind to tissue macromolecules evoking cytotoxicity. However, the specific sites of macromolecular proteins are not known and this was investigated using microsomal protein and hemoglobin. The results indicate that 2,3- and 3,4-epoxide bind to macromolecules at different rates. The 3,4-epoxide is more reactive, binding covalently to microsomal protein at the site of its synthesis, whereas bromobenzene 2,3-epoxide is more stable, leaving the microsomal protein compartment and binding covalently to soluble protein, i.e., the hemoglobin beta chain. Structural analysis with fingerprint mapping of the hemoglobin beta chain after pretreatment with cysteine and histidine blocking agents such as p-nitrophenacyl bromide, 2-bromoethylamine hydrobromide and diethylprocarbonate indicated that the 2,3-epoxide preferentially binds to the cysteinyl residue, whereas the 3,4-epoxide binds to the histidinyl residue. This difference in binding of the 2,3- and 3,4-bromobenzene epoxides may be an important factor in determining the degree of their cytotoxicity.
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