CHEMOPREVENTION OF COLON CARCINOGENESIS BY ORGANOSULFUR COMPOUNDS

It has been reported that several naturally occurring and related synt hetic 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 an ethole trithione, diallyl disulfide, N-acetylcysteine, and taurine, ad ministered in AIN-76A diet, on azoxymethane (AOM)-induced neoplasia we re investigated in male F344 rats. Also, the effects of these agents o n the activities of phase II enzymes, namely glutathione S-transferase (GST), NAD(P)H-dependent quinone reductase, and UDP-glucuronosyl tran sferase, in the liver and colonic mucosa and tumors were assessed. The MTD levels of anethole trithione, diallyl disulfide, N-acetylcysteine , and taurine were determined in male F344 rats and found to be 250, 2 50, 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 t hose 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 . Colonic mucosal and tumor and liver enzyme activities were measured in animals fed 80% MTD levels of each test agent. Colon tumors were su bjected to histopathological evaluation and classified as invasive or noninvasive adenocarcinomas. Colon tumor incidence (percentage of anim als with tumors) and tumor multiplicity (tumors/animal) were compared among various dietary groups. The results indicated that administratio n of 200 ppm (80% MTD) anethole trithione significantly inhibited the incidence and multiplicity of both invasive and noninvasive adenocarci nomas, whereas feeding of 100 ppm (40% MTD) anethole trithione or 100 (40% MTD) or 200 ppm (80% MTD) diallyl disulfide suppressed only invas ive adenocarcinomas of the colon. Although diets containing N-acetylcy steine and taurine inhibited colon tumor multiplicity, the effect was somewhat marginal. GST, NAD-(P)H-dependent quinone reductase, and UDP- glucuronosyl transferase activities in colonic mucosa and tumor and li ver were significantly elevated in animals fed anethole trithione or d iallyl disulfide, compared to those fed the control diet. N-Acetylcyst eine and taurine slightly but significantly increased only the GST act ivity in the liver. Although other mechanisms are not excluded, inhibi tion of AOM-induced colon carcinogenesis by anethole trithione and dia llyl disulfide may be associated, in part, with increased activities o f phase II enzymes such as GST, NAD(P)H-dependent quinone reductase, a nd UDP-glucuronosyl transferase in the liver and colon.