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Mechanism of Protection against Aflatoxin Tumorigenicity in Rats Fed 5-(2-Pyrazinyl)-4-methyl-1,2-dithiol-3-thione (Oltipraz) and Related 1,2-Dithiol-3-thiones and 1,2-Dithiol-3-ones¹

Departments of Environmental Health Sciences [T. W. K., P. A. E., P. M. D.] and Pharmacology and Molecular Sciences [T. W. K.], Johns Hopkins Medical Institutions, Baltimore, Maryland 21205; Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts 02118 [J. D. G.]; and Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03756 [B. D. R.]

1,2-Dithiol-3-thiones, reported constituents of cruciferous vegetables, are five-membered cyclic sulfur-containing compounds with antioxidant, chemotherapeutic, and chemoprotective activities. The effects of dietary administration of a substituted 1,2-dithiol-3-thione, oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione], a potent antischistosomal agent, on aflatoxin B₁ (AFB₁) metabolism, DNA adduct formation, and hepatic tumorigenesis were examined in male F344 rats. Rats were fed graded doses of oltipraz (0.01–0.1%) for 4 wk. During the second and third wk of oltipraz feeding rats were gavaged with 250 µg of AFB₁/kg five times a wk. Rats were finally restored to control diet 1 wk after cessation of AFB₁ dosing. At 4 months focal areas of hepatocellular alteration were identified and quantitated by staining sections of liver for -glutamyl transpeptidase activity. Treatment with oltipraz at all doses reduced by >90% the volume of liver occupied by -glutamyl transpeptidase-positive foci. Levels of AFB₁ bound to hepatic DNA were reduced between 40 and 80% in animals fed increasing doses of dietary oltipraz (0.01–0.1%) for 1 wk prior to a single exposure to AFB₁. Feeding of the higher levels of oltipraz led to marked increases in the specific activity of glutathione S-transferases, presumably serving to facilitate the detoxication of the ultimate electrophilic form of AFB₁, the 8,9-oxide. At low dietary concentrations of oltipraz (0.01%), the only inductive effects seen were on the activities of selected cytochrome P-450 monooxygenases. Therefore, the protection afforded by oltipraz may be due to both the enhancement of electrophile detoxication pathways as well as modified oxidative metabolism of AFB₁. In in vitro metabolism studies with hepatic post-mitochondrial supernatant, low-dose oltipraz pretreatment facilitated the oxidative production of aflatoxins P₁ and Q₁, but not M₁, from AFB₁. High-dose (0.1%) oltipraz pretreatment enhanced the primary metabolism of AFB₁ to aflatoxins P₁, M₁, and Q₁ as well as the formation of chloroform-insoluble metabolites. Feeding studies with a series of 1,2-dithiol-3-thione and 1,2-dithiol-3-one derivatives of oltipraz demonstrated that the inductive activity for cytochrome P-450-dependent monooxygenases and electrophile detoxication enzymes, such as glutathione S-transferases, could be readily separated by minor modifications of the 1,2-dithiol-3-thione structure. The unsubstituted 1,2-dithiol-3-thione nucleus strongly induced electrophile detoxication enzymes, but not the monooxygenases, and was the most effective inhibitor of the binding of AFB₁ to hepatic DNA in vivo. The high potency, low toxicity, and selectivity of enzyme inductive effects may render some of the 1,2-dithiol-3-thiones as excellent compounds for chemoprotection in humans.

¹ Supported by grants from the American Cancer Society (SIG-3), American Institute for Cancer Research, Biothrust, and USPHS (CA 39416). Preliminary accounts of this work were presented at the 1986 Annual Meeting of the American Association for Cancer Research (1).

² Recipient of NIH Research Career Development Award CA 01230. 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 1/21/87. Revised 5/ 4/87. Accepted 5/18/87.

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