Decreased hepatobiliary secretion of inorganic mercury, its deposition and toxicity in the Eisai hyperbilirubinemic rat with no hepatic canalicular organic anion transporter
Decreased hepatobiliary secretion of inorganic mercury, its deposition and toxicity in the Eisai hyperbilirubinemic rat with no hepatic canalicular organic anion transporter
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DOI：
10.1016/s0300-483x(97)00170-4
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发表时间：
1998-02-20
期刊：
影响因子：
4.5
通讯作者：
Arizono, K
中科院分区：
文献类型：
--
作者：
Sugawara, N;Lai, YR;Arizono, K
卫材高胆红素血症(EHB)大鼠：从SD大鼠近交系培育而来的一种新的突变品系，不表达小管多药耐药蛋白(CMRP)，缺乏小管多特异性有机阴离子转运体(CMOAT)活性。静脉注射汞-203(40mU/kg，含汞40mU/kg)。四只雄性SD和EHB大鼠。还原型谷胱甘肽(GSH)在SD和EHB大鼠胆汁中的排泄量分别为426和2ug/胆汁，作用15min。Hg203在EHB大鼠胆汁中的排泄量为SD大鼠的1/4。然而，两种菌株对汞-203的肝脏摄取没有差异。其他大鼠皮下注射(S.C.)含汞-203的氯化汞溶液(0.2 mg/kg和1.6 mg/kg)。给SD和EHB大鼠注射0.2 mg/kg后4天左右，肝脏中分别约占总剂量的3%和13%。肝上清汞主要在Sephadex柱的空隙中被回收。注射1.6 mg/kg后2天左右，SD和EHB大鼠的上述值分别为3%和23%。保留率的增加刺激了肝脏金属硫蛋白(MT)的诱导，并增加了Sephadex柱上MT区汞的比例。另一方面，汞-203在EHB大鼠胆汁中的排泄量约为SD大鼠的1/6~1/4。注射1.6 mg/kg后，EHB大鼠肝肾功能恶化。尤其是肾小管严重坏死。我们的结果提示，胆汁中无机汞的分泌可能部分受三磷酸腺苷依赖的转运系统--谷胱甘肽-S共轭输出泵(GS-X泵)的调节。显著减少排泄刺激肝脏对无机汞的滞留。然而，肝脏病变的预测性较差。MT的诱导可降低金属对肝细胞的毒性。(C)1998爱思唯尔爱尔兰科学有限公司。保留所有权利。
Eisai hyperbilirubinemic (EHB) rats: a new mutant strain inbred from Sprague-Dawley (SD) rats, show no inherent expression of the canalicular multidrug resistance protein (cMrp) and lack canalicular multispecific organic anion transporter (cMOAT) activity. A sample of Hg-203 (40 mu Ci With 40 mu g Hg/kg) was injected intravenously (i.v.) into four male SD and EHB rats. Biliary excretion of reduced-glutathione (GSH) was 426 and 2 mu g/bile for 15 min in the SD and EHB rats, respectively. Biliary excretion of Hg-203 for 45 min in EHB rats significantly decreased to 1/4 of that of the SD rats. However, there was no difference in the hepatic uptake of Hg-203 between the two strains. Other rats were injected subcutaneously (s.c.) with HgCl2 solution (at 0.2 and 1.6 mg/kg) containing Hg-203. Some 4 days after the injection of 0.2 mg/kg, about 3 and 13% of the total dose was found in the liver in SD and EHB rats, respectively. The hepatic supernatant Hg was recovered mainly in the void volume of a Sephadex column. Some 2 days after the injection of 1.6 mg/kg, these values were 3 and 23% in SD and EHB rats, respectively. The increased retention stimulated hepatic metallothionein (MT) induction and increased the proportion of Hg in the MT region on the Sephadex column. On the other hand, biliary excretion of Hg-203 for 15 min in EHB rats was about 1/6-1/4 of that in SD rats. With the injection of 1.6 mg/kg, hepatic and renal functions worsened in EHB rats. In particular, severe necrosis was found in the renal tubules. Our results suggest that biliary secretion of inorganic Hg may be partly regulated by the ATP-dependent transport system, the glutathione S-conjugate export pump (GS-X pump) composed of Mrp and MOAT. Significantly decreased excretion stimulates hepatic retention of inorganic Hg. However, the hepatic lesions are less predictive. The MT induction may reduce the toxicity of metal to the liver cells. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.