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Citrus Auraptene Exerts Dose-dependent Chemopreventive Activity in Rat Large Bowel Tumorigenesis: The Inhibition Correlates with Suppression of Cell Proliferation and Lipid Peroxidation and with Induction of Phase II Drug-metabolizing Enzymes¹

First Department of Pathology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293 [T. T., M. M., T. O., S. O.]; First Department of Pathology, Gifu University School of Medicine, Gifu 500-8076 [K. Ka.]; Department of Biochemistry, Gifu Pharmaceutical University, Gifu 502-0003 [M. K., A. H.]; Department of Biotechnological Science, Faculty of Biology-Oriented Science and Technology, Kinki University, Wakayama 649-6433 [A. M., K. Ko.]; Research and Development Division, Wakayama Agricultural Processing Research Corp., Wakayama 649-6112 [W. K., Y. T., H. Y.]; First Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-0841 [T. Y.]; and Department of Food Science and Technology, Faculty of Agriculture, Kyoto University, Sakyo-ku Kyoto 606-8224 [H. O.], Japan

In our previous short-term experiment, Citrus auraptene inhibited the development of azoxymethane (AOM)-induced aberrant crypt foci, which are precursor lesions for colorectal carcinoma. In the present study, the possible inhibitory effect of dietary administration of auraptene was investigated using an animal colon carcinogenesis model with a colon carcinogen AOM. Male F344 rats were given s.c. injections of AOM (15 mg/kg body weight) once a week for 3 weeks to induce colon neoplasms. They also received diets containing 100 or 500 ppm auraptene for 4 weeks in groups of "initiation" feeding, starting 1 week before the first dosing of AOM. The diets containing auraptene were also given to rats for 38 weeks in groups of "postinitiation" feeding. At the termination of the study (38 weeks), dietary administration of auraptene caused dose-dependent inhibition in AOM-induced large bowel carcinogenesis. Auraptene feeding during the initiation phase reduced the incidence of colon adenocarcinoma by 49% at 100 ppm (P = 0.099) and 65% at 500 ppm (P = 0.0075). Auraptene administration during the postinitiation phase inhibited the incidence of colon adenocarcinoma by 58% at 100 ppm (P = 0.021) and 65% at 500 ppm (P = 0.0075). Also, the multiplicity of colon carcinoma was significantly reduced by initiation feeding at a dose level of 500 ppm (P < 0.01) and postinitiation feeding at a level of 100 and 500 ppm (P < 0.05 and P < 0.01, respectively). Feeding of auraptene suppressed the expression of cell proliferation biomarkers (ornithine decarboxylase activity and polyamine content) in the colonic mucosa and reduced the production of aldehydic lipid peroxidation [malondialdehyde and 4-hydroxy-2(E)-nonenal]. In addition, auraptene increased the activities of Phase II drug-metabolizing enzymes (glutathione S-transferase and quinone reductase) in the liver and colon. These findings suggest that the inhibitory effects of auraptene on AOM-induced colon tumorigenesis at the initiation level might be associated, in part, with increased activity of Phase II enzymes, and those at the postinitiation stage might be related to suppression of cell proliferation and lipid peroxidation in the colonic mucosa.

¹ This work was supported in part by a Grant-in-Aid for the Second Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health and Welfare in Japan; a Grant-in-Aid for Cancer Research from the Ministry of Health and Welfare in Japan; a Grant-in-Aid from the Ministry of Education, Science and Culture of Japan; a grant from the Japanese Research and Development Association for New Food Creation in 1996; a grant from the Program for Promotion of Basic Research Activities for Innovative Biosciences, and Grant C98-1 for Collaborative Research from Kanazawa Medical University.

² To whom requests for reprints should be addressed, at First Department of Pathology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293, Japan. Phone: 81-76-286-2211; Fax: 81-76-286-6926; E-mail: takutt@kanazawa-med.ac.jp.

Received 12/29/97. Accepted 4/21/98.

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