Mutagenicity of the mercapturic acid and other S-containing derivatives of hexachloro-1,3-butadiene.
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/micrograms 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 beta-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-mercaptoacetic acid and pentachlorobutadienyl-methylthioether) did not reveal significant 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 beta-lyase was observed.
D000111:Acetylcysteine / Q000378:metabolism*; D002070:Butadienes / Q000378:metabolism* / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D009152:Mutagenicity Tests; D009153:Mutagens; D012486:Salmonella typhimurium; D013329:Structure-Activity Relationship
D002070:Butadienes; D009153:Mutagens; C001335:hexachlorobutadiene; D005978:Glutathione; D000111:Acetylcysteine