Mutagenicity of amino acid and glutathione S-conjugates in the Ames test.
The mutagenicity of the glutathione S-conjugate S-(1,2-dichlorovinyl)glutathione (DCVG), the cysteine conjugates S-(1,2-dichlorovinyl)-L-cysteine (DCVC) and S-(1,2-dichlorovinyl)-DL-alpha-methylcysteine (DCVMC), and the homocysteine conjugates S-(1,2-dichlorovinyl)-L-homocysteine (DCVHC) and S-(1,2-dichlorovinyl)-DL-alpha-methylhomocysteine (DCVMHC) was investigated in Salmonella typhimurium strain TA2638 with the preincubation assay. DCVC was a strong, direct-acting mutagen; the cysteine conjugate beta-lyase inhibitor aminooxyacetic acid decreased significantly the number of revertants induced by DCVC; rat renal mitochondria (11,000 X g pellet) and cytosol (105,000 X g supernatant) with high beta-lyase activity increased DCVC mutagenicity at high DCVC concentrations. DCVG was also mutagenic without the addition of mammalian activating enzymes; the presence of low gamma-glutamyltransferase activity in bacteria, the reduction of DCVG mutagenicity by aminooxyacetic acid, and the potentiation of DCVG mutagenicity by rat kidney mitochondria and microsomes (105,000 X g pellet) with high gamma-glutamyltransferase activity indicate that gamma-glutamyltransferase and beta-lyase participate in the metabolism of DCVG to mutagenic intermediates. The homocysteine conjugate DCVHC was only weakly mutagenic in the presence of rat renal cytosol, which exhibits considerable gamma-lyase activity, this mutagenic effect was also inhibited by aminooxyacetic acid. The conjugates DCVMC and DCVMHC, which are not metabolized to reactive intermediates, were not mutagenic at concentrations up to 1 mumole/plate. The results demonstrate that gamma-glutamyltransferase and beta-lyase are the key enzymes in the biotransformation of cysteine and glutathione conjugates to reactive intermediates that interact with DNA and thereby cause mutagenicity.
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000633:toxicity; D000818:Animals; D013437:Carbon-Sulfur Lyases; D003545:Cysteine / Q000031:analogs & derivatives* / Q000633:toxicity; D005978:Glutathione / Q000031:analogs & derivatives* / Q000633:toxicity; D006710:Homocysteine / Q000031:analogs & derivatives / Q000633:toxicity; D007668:Kidney / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D008190:Lyases / Q000378:metabolism*; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects; D013329:Structure-Activity Relationship; D005723:gamma-Glutamyltransferase / Q000378:metabolism*
D006710:Homocysteine; C051126:S-(1,2-dichlorovinyl)homocysteine; C049705:S-1,2-dichlorovinyl-N-acetylcysteine; C039961:S-(1,2-dichlorovinyl)cysteine; C041464:S-(1,2-dichlorovinyl)glutathione; D005723:gamma-Glutamyltransferase; D008190:Lyases; D013437:Carbon-Sulfur Lyases; C019969:S-alkylcysteine lyase; D005978:Glutathione; D003545:Cysteine; D000111:Acetylcysteine