Effects of Timing and Quantity of Chronic Dietary Ethanol Consumption on A/oxy methane-induced Colonie Carcinogenesis and Azoxymethane Metabolism in Fischer 344 Rats1

EpidemiolÃ3gica!studies have shown an association between consump tion of alcoholic beverages and carcinoma of the large bowel, but studies in experimental models of colonie carcinogenesis have yielded conflicting results. We assessed the effects on azoxymethane-induced colonie carci nogenesis of both timing of chronic dietary ethanol consumption relative to carcinogen administration and quantity of ethanol consumption. Tenweek-old male Fischer 344 rats were given 11%, 22%, or 33% of calories as reagent ethanol or no ethanol by pair feeding with Lieber-DeCarlitype liquid diets providing comparable total carbohydrates, proteins, fats, and calories. Ten weekly s.c. injections of the bowel carcinogen azoxymethane (AOM), 7 mg/kg, were given to all rats in weeks 1-10. Three experimental groups were given their respective ethanol diet during acclimatization and AOM administration (preinduction and induction phases) and then were given the no-ethanol diet from week 11 until sacrifice in week 26 (postinduction phase). Three other groups received the no-ethanol diet during acclimatization and AOM administration and then were changed to their respective ethanol diet until sacrifice. The control AOM group received the no-ethanol diet throughout the study. Suppression of colonie tumorigenesis occurred in the groups with high levels of chronic dietary ethanol consumption during acclimatization and AOM administration: in the 33% and 22% diet groups, the prevalence of colonie tumors was 3% and 20% as compared with 50% in control (P < 0.001 and /' < 0.02, respectively). Tumorigenesis in the left colon was more affected than in the right colon, as tumor prevalence in the left colon was decreased in both the 33% and 22% diet groups (0% in both versus 24% in control, /' < 0.005), whereas prevalence in the right colon was decreased only in the 33% diet group (3% versus 38%, P < 0.001). By contrast, prevalence of colonie tumors in the 11% diet group was not significantly different from control. Chronic dietary ethanol consumption after AOM administration had no effect on tumor outcome, regardless of quantity of consumption. In an analogous study of [I4C]AOM metab olism in rats fed the 33% diet during acclimatization and AOM admin istration, I4<'<).,was exhaled at a slower rate than in rats fed no-ethanol diet (P = 0.05), indicating suppression of AOM metabolism. By contrast, rats changed from the 33% diet to no-ethanol diet for 12 h prior to the dose of (I4C]AOM metabolized the carcinogen at a faster rate, and exhaled a larger amount as I4('(). than control (P = 0.05), indicating loss of suppression with cessation of ethanol intake and enzyme induction. Our findings suggest that chronic dietary ethanol effects on experimental colonie tumorigenesis with azoxymethane are: (a) due to mechanisms affecting the preinduction and/or induction phase, including carcinogen metabolism; (b) unrelated to postinduction events such as tumor promo tion and progression; and (c) dependent on ethanol dose with a threshold for inhibition of tumorigenesis which is mediated by ethanol inhibition of carcinogen metabolism.