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Transcriptional Control of Glutathione S-Transferase Gene Expression by the Chemoprotective Agent 5-(2-Pyrazinyl)-4-methyl-1,2-dithiole-3-thione (Oltipraz) in Rat Liver¹

Oncology Center [N. E. D.] and Department of Environmental Health Sciences [P. A. E., T. W. K.] and Pharmacology and Molecular Sciences [T. W. K.], Johns Hopkins Medical Institutions, Baltimore, Maryland 21205

The substituted 1,2-dithiole-3-thione oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione] protects against the acute and chronic toxicities of many xenobiotics, including aflatoxin B₁, in rodents. These protective effects are mediated, in part, through elevation of glutathione S-transferase (GST) activities. Because studies by Coles et al. [Carcinogenesis (Lond.), 6: 693–697, 1985] suggested that the detoxication of aflatoxin through conjugation with glutathione is principally catalyzed by GST homodimer YaYa, we have investigated the regulation of the gene coding for the Ya subunit in the liver of F344 rats following dietary administration of oltipraz. Overall GST activity, as measured by conjugation with 1,2-dichloro-4-nitrobenzene or 1-chloro-2,4-dinitrobenzene, as well as the levels of GST Ya protein, was elevated 1.5-fold by 24 h and maximally (2.7- to 3.5-fold) and persistently after 5 days on a purified diet supplemented with 0.075% oltipraz. Steady state mRNA levels for GST subunit Ya, as quantified by slot blot analysis using rat liver GST complementary DNA clone pGTB38, were also elevated by 24 h, with a maximal elevation of 3-fold observed at 3 days. However, mRNA levels decreased therafter, despite continued feeding of oltipraz. Northern blot analyses demonstrated that oltipraz did not alter the size of GST mRNA. Transcriptional activity of the GST Ya gene, as determined by nuclear run-off analysis, was increased 2-fold after 24-h feeding of oltipraz, was maximally induced 2.4-fold at 3 days, and returned to near control levels at 7 days, despite sustained feeding of oltipraz. Modulation of GST activity by oltipraz was not accompanied by changes in the methylation pattern at internal sites of the GST Ya gene. These results show that the initial induction of hepatic GST activity during oltipraz exposure correlates with changes in steady state levels of GST mRNA and rates of GST gene transcription; however, the continued elevation of GST enzymatic activities and GST Ya protein levels in the face of declining GST Ya mRNA levels and transcription rates suggests that additional mechanisms may be involved in regulating GST Ya expression by oltipraz.

¹ Supported by grants from the American Cancer Society (SIG-3) and USPHS (CA 39416 and CA 44530). N. E. D. is partially supported by American Cancer Society Clinical Oncology Development Award 89-128 and a Merck Clinical Scientist Award. T. W. K. is a recipient of NIH Research Career Development Award CA 01230.

² To whom requests for reprints should be addressed, at Department of Environmental Health Sciences, Johns Hopkins School of Hygiene and Public Health, 615 N. Wolfe Street, Baltimore, MD 21205.

Received 8/15/89. Revised 12/18/89.

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