Role of glutathione S-transferase Mu (GSTM1) in styrene-7,8-oxide toxicity and mutagenicity

Alison J. Shield, Barbara J S Sanderson

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

In the human glutathione S-transferase (GST) mu gene family, homozygous deletion of GSTM1 is the null phenotype (frequency of ∼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 GSTM-deficient lines being more sensitive. The IC50s 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 × 10-5, and that of GSTM1-proficient cell lines was 3 × 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.

Original languageEnglish
Pages (from-to)285-289
Number of pages5
JournalEnvironmental and Molecular Mutagenesis
Volume37
Issue number4
DOIs
Publication statusPublished - 2001
Externally publishedYes

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