Gao Yi, Pei Qiu-ling, Li Guo-xing, Han Guang, Tian Feng-jie, Qin Xiu-jun, Zhang Rui, Hou Wen-sheng, Li Xiu-yun
Department of Toxicology, Shanxi Medical University, Taiyuan 030001, China.
Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2006 May;24(5):278-80.
To investigate the role of multidrug resistant protein 2 (MRP2) and glutathione (GSH) cotransport system in hepatic arsenic metabolism in rats.
Thirty healthy Wistar rats were divided randomizedly into five groups. The first group was the control group and the rats in this group were administered with normal saline. In the second, third and fourth group the rats were administered with 4, 10 and 20 mg As(+)3/kg BW of sodium arsenite respectively every other day for two weeks. The fifth group was the benzene-soluble organics (BSO) intervention group and in this group the rats were administered with 2 mmol/kg BW BSO intraperitoneally every day three days before the end of the experiment. The other treatment was the same as in other groups. All rats were sacrificed two weeks after the treatments. Arsenic contents in bile, liver and blood were detected by atomic absorption spectroscopy (AAS), and the expression of MRP2 in the membrane of hepatocyte was determined by Western-blot analysis.
The level of total arsenic (including organic arsenic and inorganic arsenic) in bile, liver and blood in all three different dose groups was higher than those in the control groups (P < 0.05). Arsenic levels of bile and liver were increased with intragastric arsenic dose. Blood arsenic levels were not significantly different in three different dose groups. Expression of hepatic MRP2 was increased with intragastric arsenic concentration. A positive correlation between biliary arsenic concentration and MRP2 levels was found in liver (r = 0.986, P < 0.05). For the rats pretreated with BSO, the biliary arsenic was significantly higher than that in the control group but lower than that in the high dose group; the liver and blood arsenic was higher than that in the control group and in the high dose group. Expression of MRP2 pretreated with BSO was decreased.
Sodium arsenite can induce expression of MRP2 and the up-regulation of MRP2 may play an important role in the bile secretion of arsenite and its metabolites. The function of MRP2 for transportation of arsenic and its metabolites is associated with the intracellular GSH level. BSO inhibits the synthesis of GSH, which weakens the function of the MRP2-GSH cotransport system and makes the liver arsenic increased.
探讨多药耐药蛋白2（MRP2）和谷胱甘肽（GSH）共转运系统在大鼠肝脏砷代谢中的作用。
将30只健康Wistar大鼠随机分为五组。第一组为对照组，给该组大鼠注射生理盐水。第二、三、四组大鼠每隔一天分别给予4、10和20mg As(+)3/kg体重的亚砷酸钠，持续两周。第五组为苯溶性有机物（BSO）干预组，在该组大鼠实验结束前三天每天腹腔注射2mmol/kg体重的BSO。其他处理与其他组相同。处理两周后处死所有大鼠。采用原子吸收光谱法（AAS）检测胆汁、肝脏和血液中的砷含量，通过蛋白质免疫印迹分析测定肝细胞质膜上MRP2的表达。
三个不同剂量组的胆汁、肝脏和血液中总砷（包括有机砷和无机砷）水平均高于对照组（P < 0.05）。胆汁和肝脏中的砷水平随灌胃砷剂量增加而升高。三个不同剂量组的血液砷水平无显著差异。肝脏MRP2的表达随灌胃砷浓度增加而升高。肝脏中胆汁砷浓度与MRP2水平呈正相关（r = 0.986，P < 0.05）。对于预先用BSO处理的大鼠，胆汁砷含量显著高于对照组，但低于高剂量组；肝脏和血液中的砷含量高于对照组且低于高剂量组。预先用BSO处理的大鼠MRP2表达降低。
亚砷酸钠可诱导MRP2表达，MRP2的上调可能在亚砷酸盐及其代谢产物的胆汁分泌中起重要作用。MRP2转运砷及其代谢产物的功能与细胞内GSH水平有关。BSO抑制GSH的合成，削弱了MRP2 - GSH共转运系统的功能，使肝脏砷含量增加。
