BSEP Transporter (ATP Binding Cassette protein B11/ABCB11)
ABCB11, more commonly referred to as BSEP (Bile Salt Export Pump) is an efflux transporter that plays an important role in the disposition of bile salts from the liver, into the bile canaliculi for export into the gut. BSEP inhibition by a drug is a major safety concern, as this can result in buildup of bile salts in the liver, leading to cholestasis. The EMA Guidance includes testing for BSEP transporter, while this is not recommended by the FDA at this time.
BSEP is predominantly expressed at high concentrations in the cholesterol-rich apical (canalicular) membrane of hepatocytes, where it functions for secretion of bile salts from the liver into the bile canaliculi . mRNA expression is found in the human testis and at low levels in the choroid plexus of the brain and kidneys .
Function, physiology and clinically significant polymorphisms
The BSEP transporter is a ~160 kDa protein with 12 putative membrane spanning domains. BSEP mediates the hepatic excretion of monovalent conjugated bile acids. BSEP has a high affinity for conjugated bile acids and a relatively poor affinity for unconjugated bile acids, in the order of: taurochenodeoxycholate ~ glychodeoxycholate > taurocholate ~ glycocholate . BSEP also has a low affinity for a limited number of drugs that are substrates for MDR1 e.g. pravastatin , although a role for BSEP in clinical drug transport has not been established.
Inhibition of BSEP is related to a decrease in bile salt secretion and in some cases, development of cholestasis. Low BSEP protein expression correlates with the C-allele at position 1457 in the ABCB11 gene . Polymorphisms in the ABCB11 gene are ethnicity dependent . In-vitro evaluations revealed 616A>G, 1674G>C, 1772A>G, and 3556G>A associated with significantly impaired taurocholate transport activity; the 890A>G variant had mildly impaired function and 3556G>A associated with reduced cell surface total protein expression compared with wild-type BSEP .
BSEP expression is regulated by FXR and increased hepatic bile acids can induce transcription Nrf2 .
Mutations in the BSEP transporter gene lead to an inheritable cholestatic disorder, Progressive Familial Intrahepatic Cholestasis type 2, characterized by severe jaundice, hepatomegaly and high plasma levels of bile acids and aminotransferases. A number of mutations are present and amongst those functionally analyzed, a majority correlate with decreased protein expression and function, altered membrane targeting and increased degradation. A milder form of PFIC2 (BRIC2) is associated with recurrent episodes of cholestasis and gallstone formation. Polymorphisms in BSEP transporter are associated with intrahepatic cholestasis of pregnancy and drug-induced cholestasis (reviewed in .
In humans, unlike in rats, there is no compensatory mechanism for the loss of this transporter. Due to this, mutations or chemical inhibitors can result in decreased biliary bile salt secretion, leading to decreased bile flow and accumulation of bile salts inside the hepatocyte, resulting in hepatotoxicities. Drugs such as bosentan, troglitazone and CI-1034 cause clinical hepatotoxicity that is related to inhibition of BSEP . Drug-induced liver injury is a relevant clinical issue, in severe cases ending in liver transplantation. Therefore, measurement of BSEP inhibition by candidate drugs is relevant to drug discovery and development .
The EMA requires that all drug candidates that are eliminated via the liver be evaluated for BSEP liability. At this time there is no FDA recommendation for the BSEP transporter.
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- Sahi, J., et al., Metabolism and transporter-mediated drug-drug interactions of the endothelin-A receptor antagonist CI-1034. Chem Biol Interact, 2006. 159(2): p. 156-68.
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