DIFFERENCES IN HEPATIC PROCESSING OF DIETARY AND INTRAVENOUSLY ADMINISTERED COPPER IN RATS

The biliary pathway represents the major excretory route for copper (C u), It has been su red that glutathione (GSH) plays a role in this pro cess, However, biliary secretion of endogenous Cu is unaffected in can alicular multispecific organic anion transporter (cmoat)/multi-drug re sistance protein (mrp2)-deficient GY/TR- rats, which is a mutant rat s train expressing defective canalicular adenosine triphosphate (ATP)-de pendent GSH-conjugate transport and which is unable to secrete GSH int o 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 increas ed 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 abo ut 35 nmol/h/100 g body wt. Clearance of an intravenous (iv) bolus of Cu-64 (250 nmol/100 g body wt) was faster in GY/TR- rats than in contr ols, but secretion of Cu-64 into bile was clearly reduced in the mutan ts, Specific activity of biliary Cu was similar in both groups, To inv estigate 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 wee ks (Cu-fed) or tap water (controls), Cu feeding resulted in an increas e of biliary Cu secretion from similar to 6 to similar to 30 nmol/h/10 0 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, He patic Cu content was similar in NW and GY/TR- rats and progressively i ncreased during Cu feeding, Our data indicate that biliary secretion o f 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 identifie d Cu-ATPase, In contrast, excess hepatic Cu after iv Cu load depends o n cmoat/mrp2 activity for rapid removal, It is concluded that iv admin istered and dietary (endogenous) Cu is, in part, processed differently by rat liver, which might be related to differences in Cu redox state .