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 enzymes.
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 enzymes.
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发表时间：
1998-06
期刊：
影响因子：
11.2
通讯作者：
Takuji Tanaka;K. Kawabata;M. Kakumoto;A. Hara;Akira Murakami;W. Kuki;Y. Takahashi;H. Yonei;M. Maeda;T. Ota;S. Odashima;T. Yamane;K. Koshimįzu;H. Ohigashi
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作者：
Takuji Tanaka;K. Kawabata;M. Kakumoto;A. Hara;Akira Murakami;W. Kuki;Y. Takahashi;H. Yonei;M. Maeda;T. Ota;S. Odashima;T. Yamane;K. Koshimįzu;H. Ohigashi
在我们之前的短期实验中，柑橘金色藤能抑制偶氮甲烷(AOM)诱导的异常隐窝病灶的发展，这些隐窝病灶是结直肠癌的前驱病变。在本研究中，使用一种含有结肠癌致癌物AOM的动物结肠癌模型，研究了饮食中给予Auapene的可能的抑制作用。雄性F344大鼠皮下注射。每周注射AOM(15 mg/kg体重)1次，连续3周诱发结肠癌。他们还接受了含100ppm或500ppm Auapene的饮食，为期4周，从第一次注射AOM前一周开始，开始“开始”喂养。在“启动后”饲养组中，还给大鼠喂食含金光烯的饲料，为期38周。在研究结束时(38周)，饮食给药对AOM诱导的大肠癌变有剂量依赖性的抑制作用。在初始阶段饲喂Aurapene可使100ppm和500ppm的结肠腺癌发病率分别降低49%(P=0.099)和65%(P=0.0075)。在启动后阶段给药，100ppm的Aurapene对结肠腺癌的发生率抑制58%(P=0.021)，500ppm的Aurapene抑制65%(P=0.0075)。此外，500ppm的初始饲喂水平(P<；0.01)和100和500ppm的初始饲喂水平(P<；0.05和P<；0.01)显著降低了结肠癌的多样性。喂饲金鱼烯可抑制细胞增殖标志物(鸟氨酸脱羧酶活性和多胺含量)在结肠粘膜中的表达，并减少乙醛类过氧化产物[丙二醛和4-羟基-2(E)-壬烯醛]的产生。此外，金鱼烯还能增加肝脏和结肠中第二相药物代谢酶(谷胱甘肽S转移酶和苯醌还原酶)的活性。这些结果提示，金雀烯在起始水平对AOM诱导的大鼠结肠肿瘤的抑制作用可能部分与II相酶活性升高有关，而在起始后阶段的抑制作用可能与抑制结肠粘膜细胞增殖和脂质过氧化有关。
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.