Journal
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Volume 321, Issue 3, Pages 1170-1178Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.106.119073
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- NCI NIH HHS [CA106101] Funding Source: Medline
- NIGMS NIH HHS [GM38149, GM54724, R01 GM041935, GM41935] Funding Source: Medline
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Bile acid accumulation in hepatocytes due to inhibition of the canalicular bile salt export pump (BSEP/ABCB11) has been proposed as a mechanism for bosentan-induced hepatotoxicity. The observation that bosentan does not induce hepatotoxicity in rats, although bosentan has been reported to inhibit rat Bsep and cause elevated serum bile acids, challenges this mechanism. The lack of hepatotoxicity could be explained if bosentan inhibited hepatocyte uptake as well as canalicular efflux of bile acids. In the current study, bosentan was found to be a more potent inhibitor of Na+-dependent taurocholate uptake in rat (IC50 5.4 mu M) than human (IC50 30 mu M) suspended hepatocytes. In addition, bosentan was a more potent inhibitor of taurocholate uptake by rat Na+-dependent taurocholate cotransporting polypeptide (Ntcp/Slc10a1) (IC50 0.71 mu M) than human NTCP (SLC10A1) (IC50 24 mu M) expressed in HEK293 cells. Thus, bosentan is a more potent inhibitor of Ntcp than NTCP, and this should result in less intrahepatocyte accumulation of bile acids in rats during bosentan treatment. To begin characterization of this species difference, two chimeric molecules were generated and expressed in HEK293 cells; NTCP (1-140)/Ntcp(141-362) and Ntcp(1-140)/NTCP141-349. The mode of bosentan inhibition was noncompetitive for Ntcp, and competitive for NTCP (K-i 18 mu M) and NTCP1-140/ Ntcp(141-362) (K-i 1.7 mu M); bosentan affected both the K m and V-max of Ntcp(1-140)/NTCP141-349 (K-i 7.0 mu M). The carboxyl portions of NTCP and Ntcp were found to confer species differences in basal taurocholate transport V-max. In conclusion, differential inhibition of Ntcp and NTCP may represent a novel mechanism for species differences in bosentan-induced hepatotoxicity.
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