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-ones.
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 micrograms 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 gamma-glutamyl transpeptidase activity. Treatment with oltipraz at all doses reduced by greater than 90% the volume of liver occupied by gamma-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.(ABSTRACT TRUNCATED AT 400 WORDS)
D016604:Aflatoxin B1; D000348:Aflatoxins / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004247:DNA / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D005982:Glutathione Transferase / Q000096:biosynthesis; D006571:Heterocyclic Compounds / Q000494:pharmacology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D011230:Precancerous Conditions / Q000139:chemically induced / Q000517:prevention & control; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D013329:Structure-Activity Relationship; D013871:Thiones / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D005723:gamma-Glutamyltransferase / Q000032:analysis
D000348:Aflatoxins; D000970:Antineoplastic Agents; D006571:Heterocyclic Compounds; D011719:Pyrazines; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1; D005723:gamma-Glutamyltransferase; D005982:Glutathione Transferase; C049325:1,2-dithiol-3-thione