Dijkstra M, Havinga R, Vonk R J, Kuipers F
Groningen Institute for Drug Studies, Department of Pediatrics, University of Groningen, The Netherlands.
Life Sci. 1996;59(15):1237-46. doi: 10.1016/0024-3205(96)00447-x.
In the present study we compared, in vivo in rats, the hepatobiliary transport of monovalent (silver:Ag) and divalent metals (zinc:Zn; cadmium:Cd) with that of copper (Cu). Cu can have two oxidation states in vivo, i.e. Cu(I) and Cu(II). Studies were performed in normal Wistar (NW) rats and mutant GY Wistar rats. The latter express defective canalicular ATP-dependent glutathione-conjugate transport (cMOAT); reduced glutathione (GSH) is virtually absent in bile of these mutants. Cd (400 nmol/100g body wt, i.v.) was rapidly secreted into bile in NW rats concommitant with a 4-fold increase in biliary GSH secretion. In contrast, biliary Cd concentrations remained below detection limits in GY rats. Injection of Zn (1500 nmol/100g body wt) did not affect Zn secretion in GY rats and resulted only in a very small increase in NW rats (recovery < 2%). The biliary secretion pattern of Ag (800 nmol/100g body wt, i.v.) was highly similar to that of Cu (260 nmol/100g body wt). A biphasic pattern composed of a rapid and slow phase was observed in NW rats for both metals with a recovery of 48.5 +/- 10.6% and 44.9 +/- 8.4% of the dose for Ag and Cu, respectively. In GY rats, the rapid phase of both Ag and Cu secretion was absent and recoveries were 23.2 +/- 3.6% and 19.7 +/- 3.2%, respectively. When Ag and Cu were administered simultaneously, the recoveries of Ag and Cu were decreased in NW and GY rats when compared to single administration. Our data indicate that divalent and monovalent metals are secreted into bile via different transport systems in the rat. The absence of Cd and Zn secretion into bile of GY rats after their i.v. administration suggest a role of cMOAT in their biliary elimination. Cu and Ag probably share common transport systems for hepatobiliary removal, being in part dependent on the presence of either GSH in bile or cMOAT activity or on both. The GSH-independent portion of transport, i.e. the slow phase, may be mediated by the newly identified Cu transporting P-type ATPase (cCOP).
在本研究中，我们在大鼠体内比较了一价金属（银：Ag）和二价金属（锌：Zn；镉：Cd）与铜（Cu）的肝胆转运情况。铜在体内可有两种氧化态，即Cu(I)和Cu(II)。研究在正常Wistar（NW）大鼠和突变型GY Wistar大鼠中进行。后者表现出小管ATP依赖性谷胱甘肽共轭转运（cMOAT）缺陷；这些突变体的胆汁中几乎不存在还原型谷胱甘肽（GSH）。在NW大鼠中，静脉注射镉（400 nmol/100g体重）后迅速分泌到胆汁中，同时胆汁中GSH分泌增加4倍。相比之下，GY大鼠胆汁中的镉浓度仍低于检测限。静脉注射锌（1500 nmol/100g体重）对GY大鼠的锌分泌没有影响，而在NW大鼠中仅导致非常小的增加（回收率<2%）。静脉注射银（800 nmol/100g体重）的胆汁分泌模式与铜（260 nmol/100g体重）非常相似。在NW大鼠中，两种金属均观察到由快速和缓慢相组成的双相模式，银和铜的剂量回收率分别为48.5±10.6%和44.9±8.4%。在GY大鼠中，银和铜分泌的快速相均不存在，回收率分别为23.2±3.6%和19.7±3.2%。当同时给予银和铜时，与单次给药相比，NW和GY大鼠中银和铜的回收率均降低。我们的数据表明，二价和一价金属通过大鼠体内不同的转运系统分泌到胆汁中。静脉注射后GY大鼠胆汁中无镉和锌分泌，提示cMOAT在其胆汁消除中起作用。铜和银可能共享肝胆清除的共同转运系统，部分依赖于胆汁中GSH的存在或cMOAT活性或两者都依赖。转运的非GSH依赖性部分，即缓慢相，可能由新发现的铜转运P型ATP酶（cCOP）介导。
