Development of Intrahepatic Cholestasis by α-Naphthylisothiocyanate in Rats

Biliary excretion of taurocholate, organic anions and vinblastine in rats with α‐naphthylisothiocyanate‐induced cholestasis

“…This discrepancy is considered to be due to the earlier time point in their study than in the present study (24 h), since Krell et al reported a timedependent decrease of the excretory maximum of TC and sulfobromophthalein up to 10 h after the administration of ANIT (250 mg/kg). 12 The maintained protein levels of Mrp2 in the ANITtreated rats are consistent with the report by Ogawa et al 26 Furthermore, we have shown that the Mrp2 is localized at the canalicular membrane without a loss from the canalicular membrane, as has been reported in various experimental cholestasis models, [6][7][8][9] and the protein levels of Bsep were also maintained in ANITinduced cholestasis.…”

“…Some of the present results were consistent with a previous report by Krell et al, in that the biliary excretion of TC and sulfobromophthalein was markedly reduced 10 h after the administration of ANIT (250 mg/kg). 12 However, although Enderle et al reported that the biliary excretion of LTC 4 was moderately decreased 6-7 h after the administration of ANIT (250 mg/kg) in the isolated perfused rat liver, 25 the extent of the decrease was not as prominent as observed in the present study. This discrepancy is considered to be due to the earlier time point in their study than in the present study (24 h), since Krell et al reported a timedependent decrease of the excretory maximum of TC and sulfobromophthalein up to 10 h after the administration of ANIT (250 mg/kg).…”

“…26 Thus, in contrast to the down-regulation of Bsep and Mrp2 in other experimental cholestasis models, 6-9 the canalicular transporters have little role in ANITinduced cholestasis. Because ANIT is known to injure bile duct epithelial cells, [10][11][12] we believe that the regurgitation of bile constituents into the vein due to the damage of bile duct epithelial cells is the major cause of the marked impairment of the biliary excretion of cholephilic compounds in ANIT-induced cholestasis. These results in the ANIT-treated rats are consistent with recently reported findings on primary biliary cirrhosis: Kojima et al reported that the canalicular expression of MRP2 is not reduced in patients with primary biliary cirrhosis; 28 and Sakisaka et al…”

“…[6][7][8][9] a-Naphthylisothiocyanate (ANIT) is known to cause cholestasis by injury to the bile duct epithelial cells. [10][11][12] Bile duct injury is considered to be caused by ANIT after Mrp2-mediated biliary excretion of its glutathione conjugate, followed by the deconjugation of glutathione in the biliary tree. 13,14 The aim of the present study was to simultaneously examine the effect of a single dose of ANIT on the biliary excretion of typical substrates of the canalicular transporters and on the amount of these transporters in rats.…”

The Inhibitory Effect of Sa3443, a Novel Cyclic Disulfide Compound, on Alpha‐naphthyl Isothiocyanate‐induced Intrahepatic Cholestasis in Rats

“…In this investigation, the inhibitory effect on bile flow reduction was observed when SA3443 administered at 1 h before and 3 and 7 h after ANIT treatment. Since the reduction of bile flow was reported to begin more than 10h after ANIT treatment (Krell et al 1982), SA3443 is considered to be effective on the process of cholestasis by ANIT toxicity. Although the mode of action of SA3443 remains to be determined, we confirmed that SA3443 had a wide spectrum of effectiveness on liver injuries.…”