EXPRESSION OF GLUTATHIONE S-TRANSFERASES YA, YB1, YB2, YC1 AND YC2 AND MICROSOMAL EPOXIDE HYDROLASE GENES BY THIAZOLE, BENZOTHIAZOLE AND BENZOTHIADIAZOLE

The effects of thiazole (TH), benzothiazole (BT) and benzothiadiazole (BZ) on the expression of hepatic glutathione S-transferases (GSTs) Ya , Yb1, Yb2, Yc1 and Yc2 and microsomal epoxide hydrolase (mEH) genes w ere compared in rats. TH treatment resulted in 4- to 24-fold increases in GST Ya mRNA levels at 24 hr posttreatment; the ED(50) value was 10 mg/kg. GST Ya mRNA levels were elevated 13-, 20, 20- and 9-fold at 12 , 24, 48 and 72 hr following 100 mg/kg of TH treatment, respectively, as compared with the control. BT was a moderate inducer of GST Ya with a maximal 18-fold increase observed, whereas BZ treatment caused a tr ansient increase in GST Ya mRNA at 12 hr posttreatment, followed by a return to a 4-fold relative increase at 24 hr or afterward. Treatment of rats with TH at the dose of 100 mg/kg resulted in an similar to 10- fold increase in either Yb1 or Yb2 mRNA levels at 24 hr posttreatment. BT-treated rats showed 7- and 3-fold increases in the GST subunit Yb1 and Yb2 mRNA levels at 24 hr posttreatment. BZ was the least effectiv e in modulating either GST Yb1 or Yb2 mRNA, resulting in <2-fold chang es. GST Yc1 and Yc2 mRNA levels were increased similar to 8-fold at th e dose of 200 mg/kg of TH. BT minimally affected GST subunit Yc1 and Y c2 mRNA levels, with a maximal 4-fold relative increase observed. BZ w as the least effective in enhancing Yc1 and Yc2 mRNA levels. Protein l evels for GST subunit Ya, Yb1, Yb2 and Yc were also elevated in respon se to TH by 3-, 2-, 2- and 2-fold, respectively. Thus, TH was effectiv e in modulating both constitutive and inducible GST gene expression. B T or BZ was much less effective in increasing the expression of GST su bunits. These RNA and Western blot analyses revealed that the levels o f major GST were differentially increased after treatment with these t hiazoles, exhibiting a rank order of GST expression of TH > BT > BZ. m EH expression by these compounds appeared to be consistent with that o f GST Ya. The mRNA levels for GST Ya, Yb1, Yb2, Yc1 and Yc2 and mEH we re also determined after treatment with triazole (TR), imidazole (IM), benzoxazole (BX), benzotriazole (BTR) or benzimidazole (BIM). TR, IM, BX or BTR caused increases in Ya, Yb1, Yc1 and Yc2 mRNA levels by 2- to 3-fold, whereas the agents failed to modulate the expression of GST Yb2. The fact that benzene, cyclohexane or n-hexane minimally affecte d the major GST or mEH mRNA levels provided evidence that certain hete rocyclic compounds are more capable of modulating GST or mEH gene expr ession than hydrocarbons. These results corroborate evidence that the thiazoles differentially stimulate GST or mEH genes, with TH being the most efficacious; that thiazoles with carbocyclic ring are much less effective in increasing GST or mEH levels than is TH; and that the cha nges in these GST and mEH levels are primarily associated with increas es in mRNA levels. Copyright (C) 1996 Elsevier Science Inc.