Preclinical/Animal Transporters

Bsep - dog

Bile salt export pump (BSEP, ABCB11) is an efflux transporter that plays an important role in the distribution of bile salts from the liver into the bile canaliculi for export into the gut. BSEP inhibition by drugs is a major safety concern, as this can result in buildup of bile salts in the liver, leading to cholestasis. BSEP is predominantly expressed at high concentrations in the cholesterol-rich apical (canalicular) membrane of hepatocytes, where it functions as an efflux pump for secretion of bile salts from the liver into the bile canaliculi [1].
DogBsep protein shows 89.4% homology with human BSEP [2] and shares a similar high affinity for the conjugated bile acid taurocholic acid (TC) [3]. Species differences have been shown in affinity for drugs, such as for pravastatin and troglitazone, where dogBsep and human BSEP had similar IC50 values, while ratBsep differed significantly [2].
Common drugs used as inhibitors in BSEP studies are cyclosporin A, troglitazone and ketoconazole [3]. Troglitazone is an antidiabetic and anti-inflammatory drug which was withdrawn from the market in 1997-2000 due to the development of cholestatic liver injury, thought to be mediated at least partially by BSEP [4].

[1.]       Cheng, X., D. Buckley, and C.D. Klaassen, Regulation of hepatic bile acid transporters Ntcp and Bsep expression. Biochem Pharmacol, 2007. 74(11): p. 1665-76.
[2.]       Yabuuchi, H., et al., Cloning of the dog bile salt export pump (BSEP; ABCB11) and functional comparison with the human and rat proteins. Biopharm Drug Dispos, 2008. 29(8): p. 441-8.
[3.]       van Beusekom, C.D., et al., The feline bile salt export pump: a structural and functional comparison with canine and human Bsep/BSEP. BMC Vet Res, 2013. 9: p. 259.
[4.]       Funk, C., et al., Cholestatic potential of troglitazone as a possible factor contributing to troglitazone-induced hepatotoxicity: in vivo and in vitro interaction at the canalicular bile salt export pump (Bsep) in the rat. Mol Pharmacol, 2001. 59(3): p. 627-35.

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