Chemoprevention of Colon Carcinogenesis by Organosulfur Compounds1

It has been reported that several naturally occurring and related syn thetic organosulfur compounds exert chemopreventive effects in several target organs in rodent models. The chemopreventive actions of 40 and 80% maximum tolerated doses (MTD) of organosulfur compounds, namely anethole trithione, diali) I disulfide, W-acelylcysteine, and taurine, administered in AIN-76A diet, on azoxymethane (AOM)-induced neopla sia were investigated in male F344 rats. Also, the effects of these agents on the activities of phase II enzymes, namely glutathione S-lransferase (GST), NAD(P)H-dependent quinone reducÃ-ase, and UDP-glucuronosyl transferase, in the liver and colonie mucosa and tumors were assessed. The MTD levels of anethole trithione, diali) I disillude. jV-acetylcysteine, and taurine were determined in male F344 rats and found to be 250,250,1500, and 1500 ppm, respectively. At 5 weeks of age, animals were fed the control diet (AIN-76A) or experimental diets containing 40 or 80% MTD levels of each test agent. All animals in each group, except those allotted for vehicle (saline) treatment, were administered AOM s.c. at a dose rate of 15 mg/kg body weight once weekly for 2 weeks. All animals were necropsied during week 52 after the second AOM injection. Colonie mucosa! and tumor and liver enzyme activities were measured in animals fed 80% MTD levels of each test agent. Colon tumors were subjected to histopathological evalu ation and classified as invasive or noninvasive adenocarcinomas. Colon tumor incidence (percentage of animals with tumors) and tumor multi plicity (tumors/animal) were compared among various dietary groups. The results indicated that administration of 200 ppm (80% MTD) anet hole trithione significantly inhibited the incidence and multiplicity of both invasive and noninvasive adenocarcinomas, whereas feeding of 100 ppm (40% MTD) anethole trithione or 100 (40% MTD) or 200 ppm (80% MTD) diali) I disulfide suppressed only invasive adenocarcinomas of the colon. Although diets containing W-acelylcysleine and taurine inhibited colon tumor multiplicity, the effect was somewhat marginal. GST, N VI)(P)H-dependent quinone reducÃ-ase,and UDP-glucuronosyl transferase ac tivities in colonie mucosa and tumor and liver were significantly elevated in animals fed anethole trithione or diali) Idisulfide, compared to those fed the control diet. ¿V-Acetylcysteine and taurine slightly but significantly increased only the GST activity in the liver. Although other mechanisms are not excluded, inhibition of AOM-induced colon carcinogenesis by anethole trithione and diali) I disulfide may be associated, in part, with increased activities of phase II enzymes such as GST, NAD(P)H-dependent quinone reducÃ-ase, and UDP-glucuronosyl transferase in Ihe liver and colon.