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

The cytochrome P450-dependent generation of reactive metabolites from 1,3-d ichloropropanol 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 o f both compounds were generated in the microsomal assay; however, only dibr omopropanol extensively depleted glutathione when glutathione S-transferase was used as the enzyme source, The cytotoxicity of dichloropropanol was bo th cytochrome P450- and glutathione-dependent, whereas that of dibromopropa nol was glutathione-dependent but largely independent of cytochrome P450. T hese results indicate that the mechanisms underlying the cytotoxicity of ha lopropanols are dependent on the nature of the halogen substitution and tha t microsomal and cellular assays for reactive metabolite generation may yie ld conflicting results, (C) 1999 Academic Press.