Aliases: ABC16, Lith1, PFIC2, PGY4, SPGP
Gene name: TP-binding cassette, sub-family B (MDR/TAP), member 11 (ABCB11)
Bile salt export pump (BSEP/Bsep) is one of the major transporters of interest in drug development due to its relevance to hepatotoxicity. Rodents, dogs and monkeys are species often used in metabolic, pharmacokinetic and toxicity studies. In order to interpret data generated in these species, it is necessary to understand the functional characteristics of the animal orthologs of human BSEP.
BSEP/Bsep is highly conserved in vertebrates. Rat, mouse and dog orthologs of human BSEP are also close relatives, sharing 82, 80, and 89.4% similarity, respectively, with the human protein [1-3].
Preclinical animals are often less sensitive than humans to bile acid-mediated drug-induced liver injury. Only about 50% of clinical incidences of hepatotoxicity are predicted using rodent models; thus, results obtained in these models are not readily translatable to the human clinical setting. Potential reasons include species differences in bile acid composition, in the metabolism and disposition of drugs, as well as in the substrate and/or inhibitor specificities of bile salt transporters. It was shown previously that although the affinities for the monovalent bile acid conjugates are very close, the preferred substrate for human BSEP is taurocholate, whereas it is taurochenodeoxycholate for the rodent ortholog . Differences among species in Bsep activity and expression levels have also been demonstrated in liver tissue as well as fresh and cryopreserved hepatocytes [5-7].
An important difference between these species is their sensitivity to impairment of Bsep transport function . Loss-of-function mutations of BSEP in humans leads to progressive intrahepatic cholestasis that is fatal unless liver transplantation is performed. However, Bsep null mice developed only mild cholestasis. The secretion of hydrophobic bile salts decreased, but the amounts of the more hydrophilic bile salts were maintained, and the levels of the less toxic tetrahydroxy bile salts, which are not normally detected, were significantly increased .
In vitro assays using either hepatocytes, sandwich cultured hepatocytes, or membrane vesicles expressing the Bsep protein showed marked inter-species differences in the inhibitory potencies of selected drugs. The conclusion of these studies was that drugs are less able to inhibit mouse Bsep than the corresponding orthologs from human or other species [10, 11].
1. Green, R.M., F. Hoda, and K.L. Ward, Molecular cloning and characterization of the murine bile salt export pump. Gene, 2000. 241(1): p. 117-23.
2. Lecureur, V., et al., Expression and regulation of hepatic drug and bile acid transporters. Toxicology, 2000. 153(1-3): p. 203-19.
3. 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.
4. Byrne, J.A., et al., The human bile salt export pump: characterization of substrate specificity and identification of inhibitors. Gastroenterology, 2002. 123(5): p. 1649-58.
5. Li, N., et al., Quantitative expression profile of hepatobiliary transporters in sandwich cultured rat and human hepatocytes. Mol Pharm, 2009. 6(4): p. 1180-9.
6. Li, N., et al., LC-MS/MS mediated absolute quantification and comparison of bile salt export pump and breast cancer resistance protein in livers and hepatocytes across species. Anal Chem, 2009. 81(6): p. 2251-9.
7. Wang, L., et al., Interspecies variability in expression of hepatobiliary transporters across human, dog, monkey, and rat as determined by quantitative proteomics. Drug Metab Dispos, 2015. 43(3): p. 367-74.
8. Wang, R., et al., Targeted inactivation of sister of P-glycoprotein gene (spgp) in mice results in nonprogressive but persistent intrahepatic cholestasis. Proc Natl Acad Sci U S A, 2001. 98(4): p. 2011-6.
9. Wang, R., et al., Compensatory role of P-glycoproteins in knockout mice lacking the bile salt export pump. Hepatology, 2009. 50(3): p. 948-56.
10. Zhang, J., et al., Inhibition of bile salt transport by drugs associated with liver injury in primary hepatocytes from human, monkey, dog, rat, and mouse. Chem Biol Interact, 2016. 255: p. 45-54.
11. Kis, E., et al., Effect of membrane cholesterol on BSEP/Bsep activity: species specificity studies for substrates and inhibitors. Drug Metab Dispos, 2009. 37(9): p. 1878-86.