Kishida H, Nakae D, Kobayashi Y, Kusuoka O, Kitayama W, Denda A, Fukui H, Konishi Y
Department of Oncological Pathology, Cancer Center, Nara Medical University, Kashihara, Japan.
Exp Toxicol Pathol. 2000 Oct;52(5):405-12. doi: 10.1016/S0940-2993(00)80071-8.
Effects of pre-administration of a choline-deficient, L-amino acid-defined (CDAA) diet on hepatocarcinogenesis initiated with diethylnitrosamine (DEN) or N-nitrosobis(2-hydroxypropyl)amine (BHP) in rats were investigated. A pre-administrating period was set as 1 week, because CDAA diet induces liver injuries by this time-point. In a time-course study, male Fischer 344 rats, 6 weeks old, received a 1-week pre-administration of choline-supplemented, L-amino acid-defined (CSAA) or CDAA diet, DEN at a dose of 100 mg/kg body weight by a single intraperitoneal injection, then CSAA or CDAA diet for up to 8 weeks, and were sacrificed 4, 6 and 8 weeks after DEN. CDAA diet administered only after DEN significantly increased the numbers of glutathione S-transferase placental form (GST-P)-positive lesions 4, 6 and 8 weeks after DEN and their sizes 6 and 8 weeks after DEN. CDAA diet administered both before and after DEN similarly increased the numbers and sizes of GST-P-positive lesions, but with a significantly greater degree than obtained by the diet administered only after DEN. In a dose response study, rats received vechicle or DEN, at a dose of 0.001, 0.01, 0.1, 1, 10, 20, 50, 100 or 200 mg/kg body weight, 1 week after the commencement of CSAA or CDAA diet, and sacrificed 8 weeks after vehicle or DEN. The significant increases of the numbers of GST-P-positive lesions were obtained after 50-200 mg/kg body weight of DEN under the CSAA diet administration, whereas those were detected after 10-200 mg/kg under CDAA diet administration. Sizes became significantly larger with only 200 mg/kg body weight of DEN in the CSAA case but with 50-200 mg/kg in the CDAA case. Male Wistar rats received a 1-week pre-administration of CSAA or CDAA diet, vehicle or BHP, at a dose of 600 or 1200 mg/kg body weight, by a single intraperitoneal injection, then CSAA or CDAA diet for 8 weeks, and were then sacrificed. The numbers of GST-P-positive lesions demonstrated significant increment with 1200 mg/kg body weight of BHP by CDAA diet administered only after BHP and, to a significantly greater degree, by the diet administered both before and after BHP. While CDAA diet administered only after BHP did not alter the sizes of GST-P-positive lesions, the diet administered both before and after 600 and 1200 mg/kg body weight of BHP significantly increased the sizes of the lesions. These results indicate that the pre- plus post-administration of CDAA diet enhances hepatocarcinogenesis initiated with DEN or BHP, more than the post-administration only, thus providing a sensitive model to detect weak liver carcinogenic potency of environmental chemicals.
研究了预先给予胆碱缺乏的L-氨基酸限定（CDAA）饮食对用二乙基亚硝胺（DEN）或N-亚硝基双（2-羟丙基）胺（BHP）引发大鼠肝癌发生的影响。预先给予期设定为1周，因为此时CDAA饮食会诱导肝损伤。在一项时间进程研究中，6周龄的雄性Fischer 344大鼠接受1周的补充胆碱的L-氨基酸限定（CSAA）或CDAA饮食的预先给予，通过单次腹腔注射给予剂量为100 mg/kg体重的DEN，然后给予CSAA或CDAA饮食长达8周，并在给予DEN后4、6和8周处死。仅在给予DEN后给予CDAA饮食，在给予DEN后4、6和8周，谷胱甘肽S-转移酶胎盘形式（GST-P）阳性病变的数量以及在给予DEN后6和8周其大小均显著增加。在给予DEN之前和之后都给予CDAA饮食，同样增加了GST-P阳性病变的数量和大小，但程度明显大于仅在给予DEN后给予该饮食的情况。在一项剂量反应研究中，大鼠在开始CSAA或CDAA饮食1周后接受载体或剂量为0.001、0.01、0.1、1、10、20、50、100或200 mg/kg体重的DEN，并在给予载体或DEN后8周处死。在CSAA饮食给药情况下，给予50 - 200 mg/kg体重的DEN后，GST-P阳性病变的数量显著增加，而在CDAA饮食给药情况下，给予10 - 200 mg/kg体重的DEN后可检测到显著增加。在CSAA情况下，仅给予200 mg/kg体重的DEN时大小显著增大，而在CDAA情况下，给予50 - 200 mg/kg体重的DEN时大小显著增大。雄性Wistar大鼠接受1周的CSAA或CDAA饮食、载体或剂量为600或1200 mg/kg体重的BHP的预先给予，通过单次腹腔注射，然后给予CSAA或CDAA饮食8周，然后处死。仅在给予BHP后给予CDAA饮食时，给予1200 mg/kg体重的BHP，GST-P阳性病变的数量显著增加，并且在给予BHP之前和之后都给予该饮食时增加程度更大。虽然仅在给予BHP后给予CDAA饮食未改变GST-P阳性病变的大小，但在给予600和1200 mg/kg体重的BHP之前和之后都给予该饮食显著增加了病变的大小。这些结果表明，CDAA饮食的预先给予加之后续给予比仅后续给予更能增强由DEN或BHP引发的肝癌发生，从而提供了一个检测环境化学物质弱肝脏致癌潜力的敏感模型。
