LACK OF BILIARY-EXCRETION OF CD LINKED TO AN INHERENT DEFECT OF THE CANALICULAR ISOFORM OF MULTIDRUG-RESISTANCE PROTEIN (CMRP) DOES NOT ABNORMALLY STIMULATE ACCUMULATION OF CD IN THE EISAI HYPERBILIRUBINEMIC (EHB) RAT-LIVER

A new mutant, the Eisai hyperbilirubinemic (EHB) rat, shows no inheren t expression of the canalicular isoform of the multidrug resistance pr otein (cMrp) in the liver. It has defective biliary secretion of organ ic anions such as bilirubin bromosulfophthalein (BSP), cysteinyl gluta thione (GSH) and bile acid sulfate and glucuronides. When rats were in jected intravenously with CdCl2, biliary excretion of Cd over 30 min w as 0.28% and 0.004% of the total dose in Sprague-Dawley (SD) and EHB r ats, respectively. Six SD rats and five EHB rats were fed a diet conta ining Cd. Bile Cd was detected at the level of 2 ng/20 min in SD rats, but not in EHB rats. There was no significant difference of hepatic C d concentration between SD and EHB rats. Furthermore, there were no si gnificant differences of renal and intestinal Cd, and hepatic and rena l metallothionein (MT) concentrations between the SD and EHB groups. B iliary excretion of reduced-GSH for 20 min was 1.3 +/- 0.3 mg and 3.6 +/- 0.9 mu g in SD and EHB rats, respectively. Our results suggest tha t hepatobiliary excretion of exogenous Cd is mediated mainly via carri er transport, including a cMrp or GSH carrier, but that the lack of th e transport pathway does not contribute to abnormal accumulation of Cd in the liver.