Dijkstra M, Kuipers F, van den Berg G J, Havinga R, Vonk R J
Groningen Institute for Drug Studies, Department of Pediatrics, University of Groningen, The Netherlands.
Hepatology. 1997 Oct;26(4):962-6. doi: 10.1002/hep.510260424.
The biliary pathway represents the major excretory route for copper (Cu). It has been suggested that glutathione (GSH) plays a role in this process. However, biliary secretion of endogenous Cu is unaffected in canalicular multispecific organic anion transporter (cmoat)/multi-drug resistance protein (mrp2)-deficient GY/TR- rats, which is a mutant rat strain expressing defective canalicular adenosine triphosphate (ATP)-dependent GSH-conjugate transport and which is unable to secrete GSH into bile. Secretion of Cu after iv Cu load is markedly impaired in GY/TR- rats when compared with normal Wistar (NW) rats. Administration, iv, of 65, 325, or 2300 nmol/100 g body wt CuSO4 dose-dependently increased Cu secretion in normal Wistar (NW) rats. Secretion rates in GY/TR rats were much lower and plateaued with higher loads at a level of about 35 nmol/h/100 g body wt. Clearance of an intravenous (iv) bolus of 64Cu (250 nmol/100 g body wt) was faster in GY/TR- rats than in controls, but secretion of 64Cu into bile was clearly reduced in the mutants. Specific activity of biliary Cu was similar in both groups. To investigate the removal of excess dietary Cu via bile, GY/TR and NW rats received water supplemented with Cu (CuSO4 8 mmol/L) for up to 12 weeks (Cu-fed) or tap water (controls). Cu feeding resulted in an increase of biliary Cu secretion from approximately 6 to approximately 30 nmol/h/100 g body wt within two weeks, both in NW and GY/TR- rats; Cu secretion also did not further increase during the course of the experiment. Hepatic Cu content was similar in NW and GY/TR- rats and progressively increased during Cu feeding. Our data indicate that biliary secretion of diet-derived Cu proceeds exclusively via a saturable Cu transporting system, which is distinct from cmoat/mrp2 and which is independent of biliary GSH. This transport may be mediated by the recently identified Cu-ATPase. In contrast, excess hepatic Cu after iv Cu load depends on cmoat/mrp2 activity for rapid removal. It is concluded that iv administered and dietary (endogenous) Cu is, in part, processed differently by rat liver, which might be related to differences in Cu redox state.
胆道途径是铜（Cu）的主要排泄途径。有人提出谷胱甘肽（GSH）在这一过程中发挥作用。然而，在胆小管多特异性有机阴离子转运体（cmoat）/多药耐药蛋白（mrp2）缺陷的GY/TR -大鼠中，内源性铜的胆汁分泌未受影响，GY/TR -大鼠是一种突变大鼠品系，其表达有缺陷的胆小管三磷酸腺苷（ATP）依赖性谷胱甘肽共轭转运体，且无法将谷胱甘肽分泌到胆汁中。与正常Wistar（NW）大鼠相比，静脉注射铜负荷后，GY/TR -大鼠的铜分泌明显受损。静脉注射65、325或2300 nmol/100 g体重的硫酸铜，正常Wistar（NW）大鼠的铜分泌呈剂量依赖性增加。GY/TR大鼠的分泌率低得多，且在较高负荷时趋于平稳，水平约为35 nmol/h/100 g体重。静脉注射一次64Cu（250 nmol/100 g体重）后，GY/TR -大鼠的清除速度比对照组快，但突变体中64Cu向胆汁中的分泌明显减少。两组胆汁铜的比活性相似。为了研究通过胆汁清除过量膳食铜的情况，GY/TR和NW大鼠饮用添加了铜（硫酸铜8 mmol/L）的水长达12周（铜喂养组）或饮用自来水（对照组）。在NW和GY/TR -大鼠中，铜喂养在两周内使胆汁铜分泌从约6 nmol/h/100 g体重增加到约30 nmol/h/100 g体重；在实验过程中铜分泌也未进一步增加。NW和GY/TR -大鼠的肝脏铜含量相似，且在铜喂养期间逐渐增加。我们的数据表明，饮食来源的铜的胆汁分泌仅通过一种可饱和的铜转运系统进行，该系统不同于cmoat/mrp2，且独立于胆汁谷胱甘肽。这种转运可能由最近鉴定出的铜ATP酶介导。相反，静脉注射铜负荷后肝脏中过量的铜快速清除依赖于cmoat/mrp2的活性。结论是，静脉注射的铜和膳食（内源性）铜在大鼠肝脏中的部分处理方式不同，这可能与铜氧化还原状态的差异有关。
