Role of glutathione S-transferase mu (GSTM1) in styrene-7,8-oxide toxicity and mutagenicity.
In the human glutathione S-transferase (GST) mu gene family, homozygous deletion of GSTM1 is the null phenotype (frequency of approximately 50% in Caucasians). In the current study, GSTM1 status was determined in human cell lines using reverse transcriptase, polymerase chain reaction, and immunochemistry. Cell lines were challenged with a range of doses of styrene-7,8-oxide (SO) and then toxicity and genotoxicity were monitored. Toxicity was determined by growth in flasks and genotoxicity by cloning in microplates in the presence/absence of 6-thioguanine, to detect mutations at the hypoxanthine phosphoribosyltransferase (hprt) locus. A SO concentration-dependent decrease in survival was observed for all cell lines, with GSTM1-deficient lines being more sensitive. The IC(50)s of deficient and proficient cell lines were 0.45 and 0.55 mM SO, respectively. The difference between survival of GSTM1-deficient and -proficient cell lines approached statistical significance. The background mutation frequency of GSTM1-deficient cell lines was 2 x 10(-5), and that of GSTM1-proficient cell lines was 3 x 10(-6). GSTM1-deficient cell lines were significantly more sensitive than GSTM1-proficient cell lines to mutation induction for concentrations up to 2.5 mM SO (P < 0.001, regression analysis). These results suggest that cell lines containing metabolically competent GSTM1 are able to efficiently use GSTM1 to conjugate SO and reduce its hazard. This supports the epidemiological evidence that GSTM1 influences sensitivity to chemical carcinogenesis and subsequent risk of cancer induction.
Shield
A J
AJ
Biotechnology, School of Medicine, Flinders University of South Australia, Bedford Park, South Australia, Australia.
Sanderson
B J
BJ
D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004852:Epoxy Compounds / Q000633:toxicity*; D005838:Genotype; D005982:Glutathione Transferase / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D020128:Inhibitory Concentration 50; D009153:Mutagens; D009154:Mutation; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D004852:Epoxy Compounds; D009153:Mutagens; D012333:RNA, Messenger; D004247:DNA; C013690:styrene oxide; D005982:Glutathione Transferase