Sekijima M, Tsutsumi T, Yoshida T, Harada T, Tashiro F, Chen G, Yu S Z, Ueno Y
Department of Toxicology and Microbial Chemistry, Faculty of Pharmaceutical Sciences, Science University of Tokyo, Japan.
Carcinogenesis. 1999 Jan;20(1):161-5. doi: 10.1093/carcin/20.1.161.
The objective of this study was to elucidate whether microcystin-LR (MC-LR), a hepatotoxic blue-green algal toxin in drinking water, is carcinogenic or possesses the ability to modulate aflatoxin B1 (AFB1)-induced hepatocarcinogenicity. In a medium-term liver bioassay, male Fischer 344 rats were given a single i.p. injection of diethylnitrosamine (DEN, 200 mg/kg) followed by an i.p. injection of MC-LR for 6 weeks after 2 weeks of DEN treatment. To study the synergism between AFB1 and MC-LR, DEN-treated rats were given an i.p. injection of AFB1 (0.5 mg/kg) dissolved in dimethyl sulfoxide (DMSO) followed by MC-LR at 2 weeks after the treatment. In a separate experiment, the rats were first given AFB1 (0.5 mg/kg) and 2 weeks later an i.p. injection of 1 or 10 microg/kg of MC-LR twice a week for 6 weeks. Most rats were subjected to a two-thirds partial hepatectomy (PH) at week 3 and were killed under anesthesia at week 8. Liver sections were analyzed for glutathione S-transferase placental form (GST-P) expression, and subjected to histopathological examination for phenotypic alteration of hepatocellular foci. In rats that did not receive DEN, MC-LR did not cause a significant increase in the numbers of GST-P-positive foci, whereas AFB1 induced a slight increase in GST-P-positive foci development. In rats given DEN, MC-LR enhanced the expression of GST-P-positive foci, as did AFB1 but no synergism was observed. Histopathological analysis revealed that the area of eosinophilic foci, a biomarker for preneoplastic liver lesion, markedly increased because of MC-LR. In rats given AFB1 as an initiator, treatment with MC-LR resulted in a synergistic increase in the development of GST-P-positive foci. These results suggest that the hepatocarcinogenicities of MC-LR and AFB1 can be predicted in experimental animals with a medium-term bioassay. Furthermore, tumor promoting activity of MC-LR was demonstrated in rats treated with AFB1.
本研究的目的是阐明饮用水中的肝毒性蓝藻毒素微囊藻毒素-LR（MC-LR）是否具有致癌性或是否具备调节黄曲霉毒素B1（AFB1）诱导的肝癌发生的能力。在一项中期肝脏生物测定中，雄性Fischer 344大鼠腹腔注射一次二乙基亚硝胺（DEN，200 mg/kg），在DEN处理2周后腹腔注射MC-LR，持续6周。为研究AFB1与MC-LR之间的协同作用，给经DEN处理的大鼠腹腔注射溶解于二甲基亚砜（DMSO）的AFB1（0.5 mg/kg），处理后2周再注射MC-LR。在另一项实验中，先给大鼠注射AFB1（0.5 mg/kg），2周后每周两次腹腔注射1或10 μg/kg的MC-LR，持续6周。大多数大鼠在第3周接受了三分之二部分肝切除术（PH），并在第8周麻醉下处死。分析肝切片中谷胱甘肽S-转移酶胎盘型（GST-P）的表达，并进行组织病理学检查以观察肝细胞灶的表型改变。在未接受DEN的大鼠中，MC-LR未导致GST-P阳性灶数量显著增加，而AFB1使GST-P阳性灶形成略有增加。在给予DEN的大鼠中，MC-LR增强了GST-P阳性灶的表达，AFB1也有同样作用，但未观察到协同作用。组织病理学分析显示，作为癌前肝脏病变生物标志物的嗜酸性灶面积因MC-LR而显著增加。在用AFB1作为启动剂的大鼠中，MC-LR处理导致GST-P阳性灶形成协同增加。这些结果表明，通过中期生物测定可在实验动物中预测MC-LR和AFB1的肝癌发生情况。此外，在接受AFB1处理的大鼠中证实了MC-LR的促肿瘤活性。
