Induction of class alpha glutathione S-transferases by 4-methylthiazole in the rat liver: role of oxidative stress

The expression of glutathione S-transferase (GST) is a crucial factor in determining the sensitivity of cells and organs in response to a variety of toxicants. Expression of class alpha GST genes by methyl-substituted thiazoles was assessed in the rat liver. Northern blot analysis revealed that 4-methylthiazole (4-MT) elevated rGSTA2, A3, A5 and M1 mRNAs in the liver by 19-, 4-, 6- and 9-fold at 24 h after treatment, respectively, as compared to control. Consecutive 3-day treatment with 4-MT resulted in 4- to 7-fold increases in rGSTA and M1 mRNAs. Multiple treatments with 5-methylthiazole (5-MT) caused marginal increases in GST mRNAs in spite of the large increases in certain GST mRNAs at 24 h. Either 4, 5-dimethylthiazole (DT) or 2,4,5-trimethylthiazole (TT) minimally affected the rGSTA and rGSTM mRNA expression at 1-3 day(s). Western blot analysis showed that 4-MT induced rGSTA1/2, rGSTA3/5 and rGSTM1 proteins by 2.6-, 2.1- and 2.1-fold at 3 days, respectively, while other methylthiazoles failed to induce the GST subunits. Starving rats were treated with a lower dose of methylthiazoles to study the role of oxidative stress in the mRNA expression. The levels in rGSTA2/3/5 mRNAs were significantly enhanced by 4-MT in starving rats, whereas rGSTM1/2 mRNAs were not further increased. Other methylthiazoles were inactive in enhancing the mRNAs in starving animals. Pretreatment of starving rats with either cysteine or methionine completely prevented the increases in class alpha GST mRNAs by 4-MT. Data showed that 4-MT induces class alpha GSTs with the increases in the mRNAs, whereas 5-methyl-, dimethyl- and trimethyl-substituted thiazoles were minimally active. Increases in the class alpha GST mRNAs by 4-MT may be associated with the oxidative stress in hepatocytes, as supported by starvation and sulfur amino acid experiments.