ATP-binding cassette subfamily C member 2 (ABCC2) and ATP-binding cassette subfamily B member 4 (ABCB4) (ABCC2/ABCB4/ABCB11)

Hepatobiliary ATP-binding cassette (ABC) transporters, primarily ABCC2 (MRP2), ABCB4 (MDR3), and the related ABCB11 (BSEP), are essential proteins located on the canalicular membrane of hepatocytes that drive the secretion of bile components. ABCC2 facilitates the transport of conjugated bilirubin and various organic anions, while ABCB4 acts as a phospholipid flippase, providing phosphatidylcholine to protect the biliary epithelium from the detergent effects of bile salts, which are themselves primarily transported by ABCB11 [3, 15, 17]. Dysfunction of these transporters, whether through genetic mutations or drug-induced inhibition, leads to a variety of cholestatic liver diseases, including progressive familial intrahepatic cholestasis (PFIC), Dubin-Johnson syndrome, and intrahepatic cholestasis of pregnancy [5, 11, 14]. These transporters are also significant in pharmacology as they mediate the efflux of numerous drugs and their metabolites, contributing to multidrug resistance in cancer and serving as a major site for drug-induced liver injury (DILI) [1, 6, 23]. Therapeutic strategies often involve the use of nuclear receptor agonists, such as farnesoid X receptor (FXR) or pregnane X receptor (PXR) ligands, to induce the expression and trafficking of these transporters to restore bile flow and detoxification capacity [10, 15, 18].

Other names

Multidrug resistance-associated protein 2 (MRP2)Multidrug resistance protein 3 (MDR3)Bile salt export pump (BSEP)Canalicular multispecific organic anion transporter (cMOAT)Canalicular ABC transportersBile acid efflux pumps

Drugs interact with these transporters by inducing their expression through the activation of nuclear receptors such as FXR, PXR, and PPAR-alpha, which upregulate the transcription of the transporter genes [10, 15, 19]. Additionally, some drugs act as competitive or non-competitive inhibitors that block the efflux of bile acids or bilirubin, leading to toxicity, while others serve as substrates that are actively cleared from the liver into the bile [6, 13, 23].