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

The expression of glutathione S-transferase (GST) is a crucial factor in de termining the sensitivity of cells and organs in response to a variety of t oxicants. Expression of class alpha GST genes by methyl-substituted thiazol es was assessed in the rat liver, Northern blot analysis revealed that 4-me thylthiazole (4-MT) elevated rGSTA2, A3, AS 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 inc reases 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-tri methylthiazole (TT) minimally affected the rGSTA and rGSTM mRNA expression at 1-3 day(s). Western blot analysis showed that 4-MT induced rGSTA1/2, rGS TA3/5 and rGSTM1 proteins by 2.6-, 2.1- and 2.1-fold at 3 days, respectivel y, 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 we re significantly enhanced by 4-MT in starving rats, whereas rGSTM1/2 mRNAs were not further increased. Other methylthiazoles were inactive in enhancin g the mRNAs in starving animals. Pretreatment of starving rats with either cysteine or methionine completely prevented the increases in class alpha GS T mRNAs by 4-MT. Data showed that 4-MT induces class alpha GSTs with the in creases in the mRNAs, whereas 5-methyl-, dimethyl- and trimethyl-substitute d thiazoles were minimally active. Increases in the class alpha GST mRNAs b y 4-MT may be associated with the oxidative stress in hepatocytes, as suppo rted by starvation and sulfur amino acid experiments. (C) 2000 Elsevier Sci ence Ireland Ltd. All rights reserved.