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

l,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 l,2-dithiol-3-thione, oltipraz |5-( 2-pyrazinyl)-4-inethyl-l,2-dithiol-3-thione|, a potent antischistosomal agent, on »fiatimi! BI (AFBi) 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 «igof AFBi/kg five times a wk. Rats were finally restored to control diet 1 wk after cessation of Al H, 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 7-glutamyl transpeptidase-positive foci. levels of AFBi 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 AFBi. 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 AFBi, the 8,9-oxide. At low dietary con centrations 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 M H,. In in vitro metabolism studies with hepatic postmitochondrial supernatant, low-dose oltipraz pretreatment facilitated the oxidative production of aflatoxins I', and Qi, but not MI, from AFBi. High-dose (0.1%) oltipraz pretreatment enhanced the primary metabo lism of AFBi to aflatoxins IV M,. and Qi as well as the formation of chloroform-insoluble metabolites. Feeding studies with a series of 1,2dithiol-3-thioneand l,2-dithiol-3-one derivatives of oltipraz demonstrated that the inductive activity for cytochrome P-450-dependent monooxygen ases and electrophile detoxication enzymes, such as glutathione .S'-transferases, could be readily separated by minor modifications of the 1,2dithiol-3-thione structure. The unsubstituted l,2-dithiol-3-thione nucleus strongly induced electrophile detoxication enzymes, but not the monoox ygenases, and was the most effective inhibitor of the binding of AFBi to hepatic DNA ¡nvivo. The high potency, low toxicity, and selectivity of enzyme inductive effects may render some of the l,2-dithiol-3-thiones as excellent compounds for chemoprotection in humans.