The nature of halogen substitution determines the mode of cytotoxicity of halopropanols

The cytochrome P450-dependent generation of reactive metabolites from 1,3-dichloropropanol and 1,3-dibromopropanol was assessed in a microsomal thiol depletion assay, while the toxicity of these compounds was assessed in rat hepatocyte cultures and in the 3T3 cell line, Thiol-depleting metabolites of both compounds were generated in the microsomal assay; however, only dibromopropanol extensively depleted glutathione when glutathione S-transferase was used as the enzyme source, The cytotoxicity of dichloropropanol was both cytochrome P450- and glutathione-dependent, whereas that of dibromopropanol was glutathione-dependent but largely independent of cytochrome P450. These results indicate that the mechanisms underlying the cytotoxicity of halopropanols are dependent on the nature of the halogen substitution and that microsomal and cellular assays for reactive metabolite generation may yield conflicting results, (C) 1999 Academic Press.