Effect of oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione] on azoxymethane-induced biochemical changes related to early colon carcinogenesis in male F344 rats.
Epidemiologic studies suggest that the consumption of cruciferous vegetables is associated with a reduced risk for several types of cancer including cancer of colon. Experimental studies indicate that dithiolthiones, naturally occurring substances in cruciferous vegetables, possess anticarcinogenic properties. 5-(2-Pyrazinyl)-4-methyl-1,2-dithiol-3-thione (oltipraz), a substituted dithiolthione, has been tested for its chemopreventive activity. We studied the effect of dietary oltipraz on liver and colonic mucosal enzymes and DNA adducts to evaluate the modulating role of this agent during the early period of azoxymethane (AOM)-induced carcinogenesis. At 6 weeks of age, groups of animals were fed the AIN-76A diet containing 0 and 300 ppm oltipraz. At 8 weeks of age, all of the animals except vehicle-treated animals were administered a subcutaneous injection of AOM (15 mg/kg body wt/week for 2 weeks). Animals intended for vehicle treatment were administered normal saline subcutaneously. Fifteen hours after the second AOM injection, six animals each from control oltipraz diet groups were sacrificed and liver and colonic mucosa from each animal were used for DNA adduct analysis. Animals intended for liver and colonic mucosal glutathione S-transferase, tyrosine specific protein kinase (TPK), and ornithine decarboxylase (ODC) enzyme assays were killed 5 days after the second AOM or saline injection. The results of this study indicated that dietary oltipraz significantly increased liver (P less than 0.001) and colonic mucosal (P greater than 0.05) weights, but had no effect on body weights (P greater than 0.05). In saline-treated animals, feeding of oltipraz significantly increased the cytosolic glutathione S-transferase (P less than 0.001) and ODC (P less than 0.05) activities in the liver and colon when compared with those fed the control diet. Although our unpublished results indicate an inhibitory role of oltipraz when fed during the initiation and postinitiation phases of intestinal carcinogenesis, the increased ODC activity may indicate a possible role of oltipraz in colon tumor promotion. Additional studies are indicated to test the antitumor properties of oltipraz administered during the postinitiation phases. AOM treatment significantly increased the TPK (P less than 0.0001) and ODC (P less than 0.01) activities in the liver and colon of animals fed the control diet. Dietary oltipraz significantly suppressed the AOM-induced TPK (P less than 0.001) activities in liver and colon and ODC (P less than 0.01) activity of colon. Analysis of nucleic acid bases, O6-methylguanine, and 7-methylguanine revealed that dietary oltipraz significantly (P less than 0.05) inhibited the AOM-induced adduct species. These results suggest that dietary oltipraz enhances the colonic and liver glutathione S-transferase activity and reduced the formation of DNA adducts. In addition, dietary oltipraz modulates liver and colonic ODC and TPK activities that have been shown to play a role in tumor promotion.
Rao
C V
CV
Division of Nutritional Carcinogenesis, American Health Foundation, Valhalla, New York 10595.
Nayini
J
J
Reddy
B S
BS
D000818:Animals; D000970:Antineoplastic Agents; D001397:Azoxymethane; D001835:Body Weight / Q000187:drug effects; D003106:Colon / Q000201:enzymology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D003600:Cytosol / Q000201:enzymology; D004247:DNA / Q000187:drug effects / Q000302:isolation & purification; D005982:Glutathione Transferase / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008745:Methylation; D009955:Ornithine Decarboxylase / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011719:Pyrazines / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D012016:Reference Values; D013871:Thiones; D013876:Thiophenes
D000970:Antineoplastic Agents; D011719:Pyrazines; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz; D004247:DNA; D005982:Glutathione Transferase; D011505:Protein-Tyrosine Kinases; D009955:Ornithine Decarboxylase; D001397:Azoxymethane