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Inhibition of CYP1A2 and CYP3A4 by Oltipraz Results in Reduction of Aflatoxin B₁ Metabolism in Human Hepatocytes in Primary Culture¹

INSERM U49, Centre Hospitalier Regional Universitaire Ponchaillou, 35033 Rennes Cedex, France [S. L., F. M., A. G.]; Biochemistry and Molecular Biology Department, University College London, London W1P6DB, United Kingdom [B. C., B. K.]; INSERM U 75, Centre Hospitalier Universitaire Necker, 75015 Paris, France [L. B., P. B.]; and Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University, Nashville, Tennessee 37232 [F. P. G.]

Dithiolethiones are thought to act as potent chemoprotective agents against aflatoxin B₁ (AFB₁)-induced hepatocarcinogenesis in the rat by inducing glutathione S-transferases (GSTs). To determine whether these antioxidants can be similarly effective in human beings, we have investigated metabolism of AFB₁ in primary human hepatocytes with or without pretreatment by oltipraz (OPZ), a synthetic derivative of the natural 1,2-dithiole-3-thione. Aflatoxin M₁ (AFM₁), glutathione conjugates of AFB₁ oxides (AFBSGs), and unchanged AFB₁ were quantitated in cultures derived from eight human liver donors. Parenchymal cells obtained from the three GST M1-positive livers metabolized AFB₁ to AFM₁ and to AFBSGs derived from the isomeric exo-and endo-8,9-oxides, whereas no AFBSGs were formed in the GST M1-null cells. Pretreatment of the cells with 3-methylcholanthrene or rifampicin, inducers of CYP1A2 and CYP3A4, respectively, caused a significant increase in AFB₁ metabolism. Although OPZ induced GST A2, and to a lesser extent GST A1 and GST M1, it decreased formation of AFM₁ and AFBSG, which involves CYP1A2 and CYP3A4. Inhibition by OPZ of AFB₁ metabolism by reducing CYP1A2 and CYP3A4 was also demonstrated by decreased activity of their monooxygenase activities toward ethoxyresorufin and nifedipine, respectively. The significant inhibition by OPZ of human recombinant yeast CYP1A2 and CYP3A4 was also shown. These results demonstrate that AFBSG can be formed by GST M1-positive human hepatocytes only, and suggest that chemoprotection with OPZ is due to an inhibition of activation of AFB₁, in addition to a GST-dependent inactivation of the carcinogenic exo-epoxide.

¹ This work was supported by the Institut National de la Santé et de la Recherche Medicale, the ligue contre le cancer comité d'Ille et vilaine, the Association pour la Recherche contre le cancer, the BIOAVENIR program, the Cancer Research Campaign (United Kingdom), and USPHS Grants CA44353 and ES00267. S. Langouët was a recipient of a fellowship from the Ministère de la Recherche et de l'Espace and was granted a short-term visiting fellowship from the European Science Foundation to carry out part of the work in the London group.

² To whom requests for reprints should be addressed.

³ Present address: National Center for Toxicological Research, Jefferson, AZ 72079-9502.

Received 6/19/95. Accepted 10/ 2/95.

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