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Inhibition by Dietary Ethanol of Experimental Colonic Carcinogenesis Induced by High-Dose Azoxymethane in F344 Rats¹

Department of Pathology and Oncology Center, The Johns Hopkins University School of Medicine and Hospital, Baltimore, Maryland 21205 [S. R. H.], and Division of Molecular Biology and Pharmacology, Naylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, New York 10595 [O. S. S., E. S. F.]

Epidemiological studies have shown an association between consumption of alcoholic beverages and increased occurrence of large bowel carcinoma, but studies in experimental models of colonic carcinogenesis have produced conflicting results. We assessed the effects of chronic dietary ethanol consumption during the preinduction and induction phase (period of acclimatization and carcinogen administration) in a high-dose azoxymethane-treated rat model (14 mg/kg/wk for 10 wk). Ten-wk-old male Fischer 344 rats were given 33% of calories as ethanol or no ethanol (controls). Pair-feeding with Lieber-DeCarli-type liquid diets provided comparable total carbohydrates, proteins, fats, and calories. After 3 wk of dietary acclimatization, injections of azoxymethane (AOM) were given s.c. to all rats in Wk 1 to 10. At necropsy in Wk 25, dramatic suppression of gastrointestinal tumorigenesis was evident in the ethanol-fed group: the prevalence of colonic tumors was 5% as compared with 91% in controls; and the prevalence of small bowel tumors was 0% versus 74% (P < 0.0001). In an analogous study of [¹⁴C]AOM metabolism, exhaled ¹⁴CO₂ was decreased in the ethanol-fed rats, indicating suppression of AOM metabolism. Similarly, in the ethanol-fed rats the levels of the DNA adducts O⁶-methylguanine and 7-methylguanine 24 h after AOM injection were reduced in the colonic mucosa to 14 ± 7% and 61 ± 11% of controls and in the liver to 80 ± 9% and 86 ± 6 of controls. By contrast, rats changed from the ethanol diet to no-ethanol diet for 12 h prior to the dose of [¹⁴C]AOM metabolized the carcinogen at a faster rate than controls, indicating loss of suppression with cessation of ethanol intake along with induction of metabolizing enzymes; DNA adduct levels were reduced in the colonic mucosa to 90 ± 13% and 76 ± 9% of controls and in the liver to 81 ± 6% and 85 ± 3% of controls. Our findings indicate that dietary ethanol during the preinduction and induction phase of the AOM model dramatically inhibits tumorigenesis, even with high dosage of carcinogen, and suggest that: (a) inhibition of tumorigenesis may result from suppression of metabolic activation of AOM and the consequent reduced formation of DNA adducts during the induction (initiation) phase of the model; (b) these antiinitiation effects of ethanol are unrelated to the epidemiological association between consumption of alcoholic beverages and large bowel cancer; and (c) mechanisms of action of agents found to modulate carcinogenesis in experimental models should be determined before the results can be generalized to human beings.

¹ This investigation was supported in part by USPHS Grants R01 CA29714 and R01 CA31012, awarded by the National Cancer Institute, Department of Health and Human Services, NIH, and in part by the Clayton Fund, The Johns Hopkins University School of Medicine.

² To whom requests for reprints should be addressed.

Received 12/29/87. Revised 3/14/88. Accepted 3/18/88.

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