Conjugation of carcinogens by theta class glutathione s-transferases: mechanisms and relevance to variations in human risk.
Conjugation of chemicals with glutathione (GSH) can lead to decreased or increased toxicity. A genetic deficiency in the GSH S-transferase mu class gene M1 has been hypothesized to lead to greater risk of lung cancer in smokers. Recently a gene deletion polymorphism involving the human theta enzyme T1 has been described: the enzyme is present in erythrocytes and can be readily assayed. A rat theta class enzyme, 5-5, has structural and catalytic similarity and the protein was expressed in the Salmonella typhimurium tester strain TA1535. Expression of the cDNA vector increased the mutagenicity of ethylene dibromide and several methylene dihalides. Mutations resulting from the known GSH S-transferase substrate 1,2-epoxy-3-(4'nitrophenoxy)propane were decreased in the presence of the transferase. Expression of transferase 5-5 increased mutations when 1,2,3,4-diepoxybutane (butadiene diepoxide), 4-bromo-1,2-epoxybutane, or 1,3-dichloracetone were added. The latter compound is a model for the putative 1,2-dibromo-3-chloropropane oxidation product 1-bromo-3-chloroacetone. These genotoxicity and genotyping assays may be of use in further studies of the roles of GSH S-transferase theta enzymes in bioactivation and detoxication and any changes in risk due to polymorphism.
Guengerich
F P
FP
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.
Thier
R
R
Persmark
M
M
Taylor
J B
JB
Pemble
S E
SE
Ketterer
B
B
D000818:Animals; D002273:Carcinogens / Q000378:metabolism* / Q000494:pharmacology; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008658:Inactivation, Metabolic; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D009152:Mutagenicity Tests; D009369:Neoplasms / Q000453:epidemiology*; D011110:Polymorphism, Genetic; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D012307:Risk Factors; D012486:Salmonella typhimurium / Q000187:drug effects
D002273:Carcinogens; D007527:Isoenzymes; D011994:Recombinant Proteins; D005982:Glutathione Transferase