Toxicity and Covalent Binding of Substituted Bromobenzenes to Isolated Hepatocytes
The hepatotoxicity of bromobenzene (1) has been associated with its metabolic activation and the subsequent covalent binding of a reactive metabolite, presumably its 3,4-oxide, to liver macromolecules (Reid and Krishna, 1973). In view of the presumed non-enzymatic nature of the covalent binding step, it was hypothesized that modulation of the reactivity of the metabolite through the use of substituent effects would lead to predictable alterations in the toxicity of the precursor bromobenzene derivatives, and this was indeed found to be the case (Toranzo et al., 1977). The hepatotoxicity of bromobenzene was increased dramatically by electron withdrawing ortho-substituents (e.g. NO2, CN, Br) and conversely was decreased by electron-donating substituents such as CH3O, CH3, or C2H5. When the metabolism of these compounds was investigated in vitro with rat liver microsomes, the substituents were found to have exactly the opposite effect, i.e., electron-donating groups increased the rate of metabolic oxidation while electron-withdrawing groups made the rates imperceptibly slow (Wiley et al., 1979).
KeywordsTrypan Blue Test Compound Covalent Binding Marker Enzyme Enzyme Release
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