Mutagenicity of the mercapturic acid and other S-containing derivatives of hexachloro-1,3-butadiene

Abstract

The main metabolic pathway of the genotoxic environmental contaminant hexachloro-1,3-butadiene (HCBD) is the direct conjugation reaction with glutathione. To establish structure-effect relationships we studied the mutagenic activity of four S-containing HCBD conjugates with and without metabolic activating enzymes (S9 mix) in Salmonella typhimurium . The N -acetyl-S-pentachlorobutadienyl-L-cysteine (mercapturic acid) was clearly mutagenic after metabolic activation; its mutagenic activity was 48.6 revertants/μg or 18.7 revertants/nmol, which is, on a molar basis, a mutagenic response 80 times greater than that of the parent compound HCBD. The mutagenic effect of the mercapturic acid rather decreased by addition to the pre-incubation system of pyridoxal 5'-phosphate, a co-factor of the enzyme β-lyase. Methyl- N -acetyl-S-pentachlorobutadienyl-D,L-homocysteinate, structurally closely related to mercapturic acid, exerted a weak mutagenic effect comparable to that of HCBD. The two S-containing HCBD metabolites (S-pentachlorobutadienyl-mer-captoacetic acid and pentachlorobutadienyl-methylthioether) did not reveal sigificant mutagenic effects. The results indicate the involvement of the enzyme N -deacetylase which catalyzes the conversion of mercapturic acid to the HCBD-cysteine conjugate. In addition a high substrate specificity of the C-S bond-cleaving enzyme β-lyase was observed.