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We investigated the effects of glutathione-S-transferase (GST) inhibitor treatment on human colon HT29 cell mRNA levels of dihydrodiol dehydrogenase (DDH), glyoxalase I, and gamma-glutamylcysteine synthetase. Time- and concentration-dependent increases in both DDH and gamma-glutamylcysteine synthetase mRNAs resulted from treatment with ethacrynic acid, ethacrynic acid/glutathione conjugate, and T.199 (gamma-glutamyl-S-(benzyl)-cysteinyl-R(-)-phenyl glycine diethyl ester), a selective GST pi inhibitor. In contrast, glutathione analogue GST alpha- and GST mu-selective inhibitors did not induce expression of these genes. Treatment with ethacrynic acid or T.199 had no effect on the mRNA levels of the glutathione-dependent glyoxalase I gene. Pretreatment of cells with buthionine-DL-sulfoximine, a gamma-glutamylcysteine synthetase inhibitor and glutathione depleter, coupled with ethacrynic acid, ethacrynic acid/glutathione conjugate, or T.199 resulted in greater levels of gamma-glutamylcysteine synthetase and DDH induction compared with single treatments. Treatment with buthionine-DL-sulfoximine alone resulted in modest increases in both gamma-glutamylcysteine synthetase and DDH expression. Analyses of DDH induction by both differential Northern hybridization with specific oligonucleotides as probes and reverse transcriptase-polymerase chain reaction amplification of products, followed by diagnostic restriction digestion with endonucleases, showed that ethacrynic acid induced multiple DDH transcripts in HT29 cells and human HepG2 and SKHep1 hepatoma cells. Possible induction mechanisms include the alteration of sulfhydryl status by the electrophilic properties of EA or by elevations of endogenously generated oxidative stress via transient removal of GST pi from the cytosolic GST pool.
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