Bile acids export pump

A familial deficiency in the bile-acid export pump, 103 which conveys bile acids from hepatocyte cytoplasm into bile canaliculi, increases the incidence of hepatocellular carcinoma in children. 

Bile salt export pump (BSEP gene symbol ABCB11) mediates the biliary excretion of nonconjugated bile salts, such as taurocholic acid, glycocholic acid and cholic acid, and therefore is responsible for the formation of the bile acid-dependent bile flow [97, 98]. Its hereditary defect results in the acquisition of PFIC2, a potentially lethal disease which requires liver transplantation [17, 81, 82, 99]. As discussed in Section 12.5.2, the inhibition of BSEP following drug administration may result in cholestasis. 

H., Sugiyama, Y., Characterization of bile acid transport mediated by multidrug resistance assodated protein 2 and bile salt export pump, Biochim. Biophys. Acta 2001, 1511, 7-16. 

Funk, C. et al. (2001) Troglitazone-induced intrahepatic cholestasis by an interference with the hepatobiliary export ofbile acids in male and female rats. Correlation with the gender difference in troglitazone sulfate formation and ihe inhibition of the canalicular bile salt export pump (Bsep) by troglitazone and troglitazone sulfate. Toxicology, 167 (1), 83-98. 

PFIC 2 This gene mutation, which is located on chromosome 2q24, impairs the canalicular bile salt export pump (BSEP), resulting in the accumulation of bile acids in hepatocytes. Laboratory tests show an increase in bile acid, AP and LAP levels with lowered gamma GT and cholesterol levels. Pruritus is common. There is histological evidence of neonatal giant cell hepatitis. Prognosis is poor. 

Yu, J., Lo, J. L., Huang, L., Zhao, A., Metzger, E., Adams, A., Meinke, P. T., Wright, S. D., and Cui, J. (2002) Lithocholic acid decreases expression of bile salt export pump through farnesoid X receptor antagonist activity. J. Biol. Chem. 277, 31441-31447. 

Ananthanarayanan, M., Balasubramanian, N., Makishima, M., Mangelsdorf, D. J., and Suchy, F. J. (2001) Human bile salt export pump promoter is transactivated by the famesoid X receptor/bile acid receptor. J. Biol. Chem. 276, 28857-28865. 

Fig. 5. Transport of bile acids in the enterohepatic circulation. The left and right sides of the figure depict a liver and intestinal cell, respectively. Bile acids (BA) are made from unesterified cholesterol (UC) in the liver. The movement of bile acids in the enterohepatic circulation is vectorial. The major transporters thought to be responsible for the entry and exit of bile acids in liver and intestinal cells are sodium/taurocholate cotransporting polypeptide (ntcp SLClOAl), bile salt export pump (bsep ABCBll), apical/sodium bile acid cotransporter (asbt SLC10A2), and organic solute transporters a/p, (Osta/P).

The estrogen receptor-subtype ERa mediates the hepatotoxicity of 17a-ethinylestradiol (EE2). Upon EE2 treatment, ERa represses the expression of bile acid and cholesterol transporters (bile salt export pump, BSEP), Na /taurocholate cotransporting polypeptide (NTCP), OATPl, OATP2, ABCG5, and ABCG8 in the liver [101]. The genetic variability of some of these transporters is well known and could explain, at least in part, the interindividual differences for the tolerability of oral contraceptives. 

Mita S, Suzuki H, Akita H, Hayashi H, Onuki R, Hofmann AF, Sugiyama Y (2006b) Inhibition of bile acid transport across Na-r/taurocholate cotransporting polypeptide (SLClOAl) and bile salt export pump (ABCB ll)-coexpressing LLC-PKl cells by cholestasis-inducing drugs. Drug Metab Dispos 34, 1575-81. 

Rodrigues AD, Lai Y, Cvijic ME, EUdn LL, Zvyaga T, Soars MG (2014). Drug-induced perturbations of the bile acid pool, cholestasis, and hepatotoxicity mechanistic considerations beyond the direct inhibition of the bile salt export pump. Drug Metab Dispos 42, 566-74. 

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