Enhancement of bacterial mutagenicity of bifunctional alkylating agents by expression of mammalian glutathione S-transferase.
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.(ABSTRACT TRUNCATED AT 250 WORDS)
Thier
R
R
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.
Müller
M
M
Taylor
J B
JB
Pemble
S E
SE
Ketterer
B
B
Guengerich
F P
FP
D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D004357:Drug Synergism; D005978:Glutathione / Q000737:chemistry / Q000187:drug effects; D005982:Glutathione Transferase / Q000187:drug effects*; D007306:Insecticides / Q000633:toxicity; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D011407:Propane / Q000031:analogs & derivatives / Q000633:toxicity; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics
D000477:Alkylating Agents; D007306:Insecticides; D009153:Mutagens; C007318:1,2-dibromo-3-chloropropane; D005982:Glutathione Transferase; D005978:Glutathione; D011407:Propane