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Preferential Increase of Glutathione S-Transferase Class Transcripts in Cultured Human Hepatocytes by Phenobarbital, 3-Methylcholanthrene, and Dithiolethiones¹

Inserm U49, Unité de Recherches Hépatologiques, Hôpital Pontchaillou, 35033 Rennes, France [F. M., O. F., S. L., B. M., A. G.]; CRC Molecular Toxicology Group, Department of Biochemistry, University College and Middlesex School of Medicine, London W1P 6DB, England [D. J. M., K. S. G., B. K.]; Department of Molecular and Cell Biology, Pennsylvania State University, University Park, Pennsylvania 16802 [C-P. D. T.]; and Department of Environmental Health Sciences, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Maryland 21205-2179 [T. W. K.]

² To whom requests for reprints should be addressed.

In rodents, a diversity of compounds are able to protect against acute and chronic toxicities of various xenobiotics including carcinogens, at least in part through induction of drug-metabolizing enzymes including glutathione S-transferase (GST) enzymes. We have posed the question as to whether or not these compounds also induce GSTs in human liver. Primary human hepatocyte cultures were exposed to phenobarbital, 3-methylcholanthrene, and two dithiolethiones [1,2-dithiole-3-thione and its 5-(2-pyrazinyl)-4-methyl derivative, oltipraz], and steady-state mRNA levels of GST classes , µ, and were determined by Northern blot analysis. After 3 daily treatments, the two dithiolethiones were the most potent inducers; phenobarbital was also effective but to a lesser extent and 3-methylcholanthrene increased GST mRNA in only 2 of the 6 samples, although it stimulated cytochrome P-450 1A2 mRNA in all cell preparations. Whatever the compound only GST A1 and/or A2 transcripts were induced. GST M1 mRNAs were not responsive or only slightly responsive, and GST P1 mRNAs, which were mostly undetectable in control cells, were not affected by treatment with any of the four chemicals. Large individual variations were observed in the level of induction of GST A1 and/or A2 mRNAs, and no sex difference could be demonstrated. These results clearly indicate that phenobarbital, 3-methylcholanthrene, and dithiolethiones are able to markedly increase mRNA levels of GST in human hepatocytes and that the GST class is preferentially involved.

¹ Supported by the Institut National de la Santé et de la Recherche Médicale, the Association pour la Recherche contre le Cancer, and the Ligue contre le Cancer, comité d'Ille et Vilaine. F. M. is a recipient of a fellowship from the Association pour la Recherche contre le Cancer.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 10/21/92. Accepted 11/24/92.

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