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Differences in hepatic processing of dietary and intravenously administered copper in rats
Author(s) -
Dijkstra M,
Kuipers F,
van den Berg G J,
Havinga R,
Vonk R J
Publication year - 1997
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.510260424
Subject(s) - copper , medicine , physiology , pharmacology , chemistry , organic chemistry
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 CuSO 4 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 64 Cu (250 nmol/100 g body wt) was faster in GY/TR ‐ rats than in controls, but secretion of 64 Cu 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 (CuSO 4 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 ∼ 6 to ∼ 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.