Experimental analysis of the mechanisms of alphanaphthylisothiocyanate-induced cholestasis in rats

Abstract

To clarify the precise mechanism of intrahepatic cholestasis by alphanaphthylisothiocyanate (ANIT), ANIT was administered (540μmol/kg) to Sprague-Dawley rats (SDR) and Eisai hyperbilirubinuria rat (EHBR). EHBR is known as a model animal of Dubin-Johnson syndrome, characterized by the impaired glutathione (GSH) and GSH-conjugated tansport via bile canalicular membranes. In SDR, the concentration of GSH in the liver tissue transiently decreased at 6 hours after oral administration of ANIT, followed by intrahepatic cholestasis. Moreover, pretreatment with phenobarbital enhanced the ANIT-induced cholestasis. On the other hand, ANIT did not cause cholestasis in EHBR, indicating impaired excretion of ANIT metabolites. In addition, the biliary excretion of sulfobromophtalein decreased when ANIT was co-infused. These results strongly suggest that ANIT may be excreted into the bile as a GSH conjugated form, and that GSH-conjugated ANIT oritsdeconjugates may cause cholestasis.