Enhancement of bacterial mutagenicity of bifunctional alkylating agents by expression of mammalian glutathione s-transferase


Autoria(s): Thier, Ricarda; Muller, Michael; Taylor, John B.; Pemble, Sally E.; Ketterer, Brian; Guengerich, F. Peter
Data(s)

01/04/1995

Resumo

Recently, we inserted the plasmid vector pKK233-2 containing rat GSH S-transferase (GST) 5-5 cDNA into Salmonella typhimurium TA1535 and found that these bacteria [GST 5-5(+)] expressed the protein and produced mutations when ethylene or methylene dihalides were added [Thier, R., Taylor, J. B., Pemble, S. E., Ketterer, B., Persmark, M., Humphreys, W. G., and Guengerich, F. P. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 8576-8580]. After exposure to the known GST 5-5 substrate 1,2-epoxy-3-(4′-nitrophenoxy)propane, the GST 5-5(+) strain showed fewer mutants than the bacteria transfected with the cDNA clone in a reverse orientation [GST 5-5(-)], suggesting a protective role of GST 5-5. However, mutations were considerably enhanced in the GST 5-5(+) strain [as compared to GST 5-5(-)] when 1,2,3,4-diepoxybutane (butadiene diepoxide) or 1,2-epoxy-4-bromobutane was added. The GST 5-5(+) and GST 5-5(-) bacterial stains showed similar responses to 1,2-epoxypropane, 3,4-epoxy-1-butene, and 1,4-dibromobutane. The results suggest that some bifunctional activated butanes are transformed to mutagenic products through GSH conjugation. We also found that the GST 5-5(+) strain showed enhanced mutagenicity with 1,4-dibromo-2,3-epoxybutane, 1,2-epoxy-3-bromopropane (epibromohydrin), and (±)-1,4-dibromo-2,3-dihydroxybutane. The possibility was considered that a 5-membered thialonium ion may be involved in the mutagenicity. Model thialonium compounds were rather stable to hydrolysis in aqueous solution at pH 7.4 and slowly alkylated 4-(4-nitrobenzyl)pyridine. The presence of a hydroxyl group β to the sulfur did not enhance reactivity. Mechanisms involving episulfonium ions are considered more likely. Potential oxidation products of the toxic pesticide 1,2-dibromo-3-chloropropane (DBCP) were also considered in this system. DBCP itself gave rather similar results in the two strains. Others have reported that oxidation of DBCP is required for mutagenicity, along with GST-catalyzed GSH conjugation [Simula, T. P., Glancey, M. J., Söderlund, E. J., Dybing, E., and Wolf, C. R. (1993) Carcinogenesis 14, 2303-2307]. The putative oxidation product 1,2-dibromopropional did not show a difference between the two strains. However, 1,3-dichloroacetone, a model for the putative oxidation product 1-bromo-3-chloroacetone, was considerably more mutagenic in the GST 5-5(+) strain.

Identificador

http://eprints.qut.edu.au/77491/

Publicador

American Chemical Society.

Relação

DOI:10.1021/tx00045a019

Thier, Ricarda, Muller, Michael, Taylor, John B., Pemble, Sally E., Ketterer, Brian, & Guengerich, F. Peter (1995) Enhancement of bacterial mutagenicity of bifunctional alkylating agents by expression of mammalian glutathione s-transferase. Chemical Research in Toxicology, 8(3), pp. 465-472.

Direitos

Copyright 1995 American Chemical Society

Fonte

School of Clinical Sciences; Faculty of Health

Palavras-Chave #1 bromo 3 chloroacetone #1 #4 dibromo 2 #3 dihydroxybutane #4 (4 nitrobenzyl)pyridine #alkylating agent #butadiene diepoxide #epibromohydrin #glutathione transferase #unclassified drug #article #bacterial mutation #mutagen testing #mutagenicity #nonhuman #salmonella typhimurium #Alkylating Agents #Animal #Drug Synergism #Glutathione #Insecticides #Organochlorine #Mutagenicity Tests #Mutagens #Propane #Rats #Support #Non-U.S. Gov't #Support #U.S. Gov't #P.H.S.
Tipo

Journal Article