Bile secretion of cadmium, silver, zinc and copper in the rat. Involvement of various transport systems.

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).