DECREASED HEPATOBILIARY SECRETION OF INORGANIC MERCURY, ITS DEPOSITION AND TOXICITY IN THE EISAI HYPERBILIRUBINEMIC RAT WITH NO HEPATIC CANALICULAR ORGANIC ANION TRANSPORTER

Eisai hyperbilirubinemic (EHB) rats: a new mutant strain inbred from S prague-Dawley (SD) rats, show no inherent expression of the canalicula r multidrug resistance protein (cMrp) and lack canalicular multispecif ic organic anion transporter (cMOAT) activity. A sample of Hg-203 (40 mu Ci With 40 mu g Hg/kg) was injected intravenously (i.v.) into four male SD and EHB rats. Biliary excretion of reduced-glutathione (GSH) w as 426 and 2 mu g/bile for 15 min in the SD and EHB rats, respectively . Biliary excretion of Hg-203 for 45 min in EHB rats significantly dec reased to 1/4 of that of the SD rats. However, there was no difference in the hepatic uptake of Hg-203 between the two strains. Other rats w ere injected subcutaneously (s.c.) with HgCl2 solution (at 0.2 and 1.6 mg/kg) containing Hg-203. Some 4 days after the injection of 0.2 mg/k g, about 3 and 13% of the total dose was found in the liver in SD and EHB rats, respectively. The hepatic supernatant Hg was recovered mainl y in the void volume of a Sephadex column. Some 2 days after the injec tion of 1.6 mg/kg, these values were 3 and 23% in SD and EHB rats, res pectively. The increased retention stimulated hepatic metallothionein (MT) induction and increased the proportion of Hg in the MT region on the Sephadex column. On the other hand, biliary excretion of Hg-203 fo r 15 min in EHB rats was about 1/6-1/4 of that in SD rats. With the in jection of 1.6 mg/kg, hepatic and renal functions worsened in EHB rats . In particular, severe necrosis was found in the renal tubules. Our r esults suggest that biliary secretion of inorganic Hg may be partly re gulated by the ATP-dependent transport system, the glutathione S-conju gate export pump (GS-X pump) composed of Mrp and MOAT. Significantly d ecreased excretion stimulates hepatic retention of inorganic Hg. Howev er, the hepatic lesions are less predictive. The MT induction may redu ce the toxicity of metal to the liver cells. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.