Tanaka T, Kawabata K, Kakumoto M, Hara A, Murakami A, Kuki W, Takahashi Y, Yonei H, Maeda M, Ota T, Odashima S, Yamane T, Koshimizu K, Ohigashi H
First Department of Pathology, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
Cancer Res. 1998 Jun 15;58(12):2550-6.
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.
在我们之前的短期实验中，柑橘奥瑞烯抑制了由氧化偶氮甲烷（AOM）诱导的异常隐窝灶的形成，这些异常隐窝灶是结直肠癌的前体病变。在本研究中，使用含有结肠致癌物AOM的动物结肠癌发生模型，研究了饮食中添加奥瑞烯可能产生的抑制作用。雄性F344大鼠每周皮下注射一次AOM（15毫克/千克体重），共注射3周以诱导结肠肿瘤。在首次注射AOM前1周开始，将它们分为“启动”喂养组，每组给予含100或500 ppm奥瑞烯的饲料4周。含奥瑞烯的饲料也在“启动后”喂养组中给予大鼠38周。在研究结束时（38周），饮食中添加奥瑞烯对AOM诱导的大肠肿瘤发生产生剂量依赖性抑制。在启动阶段给予奥瑞烯，100 ppm时结肠腺癌的发生率降低了49%（P = 0.099），500 ppm时降低了65%（P = 0.0075）。在启动后阶段给予奥瑞烯，100 ppm时结肠腺癌的发生率抑制了58%（P = 0.021），500 ppm时抑制了65%（P = 0.0075）。此外，在启动阶段给予500 ppm剂量水平的奥瑞烯以及在启动后阶段给予100和500 ppm剂量水平的奥瑞烯，结肠癌的发生数量均显著减少（分别为P < 0.01、P < 0.05和P < 0.01）。给予奥瑞烯可抑制结肠黏膜中细胞增殖生物标志物（鸟氨酸脱羧酶活性和多胺含量）的表达，并减少醛类脂质过氧化产物（丙二醛和4-羟基-2（E）-壬烯醛）的产生。此外，奥瑞烯可增加肝脏和结肠中Ⅱ相药物代谢酶（谷胱甘肽S-转移酶和醌还原酶）的活性。这些发现表明，奥瑞烯在启动水平对AOM诱导的结肠肿瘤发生的抑制作用可能部分与Ⅱ相酶活性增加有关，而在启动后阶段的抑制作用可能与抑制结肠黏膜中的细胞增殖和脂质过氧化有关。
