Expression of mammalian glutathione S-transferase 5-5 in Salmonella typhimurium TA1535 leads to base-pair mutations upon exposure to dihalomethanes
Thier, R., Taylor, J. B., Pemble, S. E., Humphreys, W. G., Persmark, M., Ketterer, B., & Guengerich, F. P. (1993) Expression of mammalian glutathione S-transferase 5-5 in Salmonella typhimurium TA1535 leads to base-pair mutations upon exposure to dihalomethanes. Proceedings of the National Academy of Sciences of the United States of America, 90(18), pp. 8576-8580.
Dihalomethanes can produce liver tumors in mice but not in rats, and concern exists about the risk of these compounds to humans. Glutathione (GSH) conjugation of dihalomethanes has been considered to be a critical event in the bioactivation process, and risk assessment is based upon this premise; however, there is little experimental support for this view or information about the basis of genotoxicity. A plasmid vector containing rat GSH S-transferase 5-5 was transfected into the Salmonella typhimurium tester strain TA1535, which then produced active enzyme. The transfected bacteria produced base-pair revertants in the presence of ethylene dihalides or dihalomethanes, in the order CH2Br2 > CH2BrCl > CH2Cl2. However, revertants were not seen when cells were exposed to GSH, CH2Br2, and an amount of purified GSH S-transferase 5-5 (20-fold excess in amount of that expressed within the cells). HCHO, which is an end product of the reaction of GSH with dihalomethanes, also did not produce mutations. S-(1-Acetoxymethyl)GSH was prepared as an analog of the putative S-(1-halomethyl)GSH reactive intermediates. This analog did not produce revertants, consistent with the view that activation of dihalomethanes must occur within the bacteria to cause genetic damage, presenting a model to be considered in studies with mammalian cells. S-(1-Acetoxymethyl)GSH reacted with 2′-deoxyguanosine to yield a major adduct, identified as S-[1-(N2-deoxyguanosinyl)methyl]GSH. Demonstration of the activation of dihalomethanes by this mammalian GSH S-transferase theta class enzyme should be of use in evaluating the risk of these chemicals, particularly in light of reports of the polymorphic expression of a similar activity in humans.
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|Item Type:||Journal Article|
|Keywords:||Chemical carcinogens, Glutathione, Mutagenicity, Mammalia, Salmonella typhimurium, Typhimurium, 1, 2 dibromoethane, carcinogen, deoxyguanosine, dibromomethane, dichloromethane, glutathione derivative, glutathione transferase, article, base pairing, conjugation, enzyme activation, enzyme assay, genetic transfection, genotoxicity, nonhuman, oxidation, priority journal, revertant, Animal, Base Composition, Base Sequence, Cloning, Molecular, Comparative Study, Escherichia coli, Ethylene Dibromide, Ethylene Dichlorides, Genetic Vectors, Human, Hydrocarbons, Halogenated, Isoenzymes, Molecular Sequence Data, Mutagenesis, Mutagens, Oligodeoxyribonucleotides, Plasmids, Polymerase Chain Reaction, Polymorphism (Genetics), Rats, Support, Non-U.S. Gov't, Support, U.S. Gov't, P.H.S., Transfection|
|Divisions:||Current > Schools > School of Design
Current > QUT Faculties and Divisions > Faculty of Health
|Copyright Owner:||Copyright 1993 National Academy of Sciences|
|Deposited On:||16 Oct 2014 00:25|
|Last Modified:||16 Oct 2014 00:25|
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