A recombinant model for assessing the role of GSTM1 in styrene-7,8-oxide toxicity and mutagenicity.
Styrene-7,8-oxide (SO) is a highly reactive epoxide able to undergo reactions with endogenous nucleophiles, such as DNA. SO is inactivated by glutathione-S-transferase M1 (GSTM1). This detoxification enzyme is absent in approximately one-half of Caucasian (49%) populations. A GSTM1 recombinant human lymphoblastoid cell line (FB7) was generated from a GSTM1 negative parental cell line (WIL2NS). GSTM1 status was determined using RT-PCR and immunochemistry. Cells were challenged with a range of SO doses and subsequent toxicity (population growth in flasks) and genotoxicity (mutations at the HPRT locus) were monitored. FB7 (GSTM1 positive) exhibited greater cell survival after SO exposure relative to the GSTM1 negative parental line. The IC50 following a 1 h exposure to SO was 0.5 mM for WIL2NS, compared to greater than 2.5 mM for FB7. The extrapolated IC50 for FB7 was 5.5 mM. Significantly fewer mutant cells were induced by SO for FB7 than for WIL2NS at equivalent doses of SO. These findings suggest that the sensitivity of cells to styrene-7,8-oxide is influenced by GSTM1 status and that a recombinant GSTM1 positive cell line can efficiently detoxify styrene-7,8-oxide.
Shield
Alison J
AJ
Department of Medical Biotechnology, School of Medicine, Flinders University of South Australia, Bedford Park, SA 5042, Australia.
Sanderson
Barbara J S
BJ
D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004852:Epoxy Compounds / Q000633:toxicity*; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D004852:Epoxy Compounds; D009153:Mutagens; D011994:Recombinant Proteins; C013690:styrene oxide; D005982:Glutathione Transferase