**2. BSEP/ABCB11: Physiological Role**

– The bile salt export pump (BSEP) is expressed in hepatocytes. While high levels of BSEP mRNA were detected in testes and lower levels were reported in other extrahepatic tissues, including trachea, prostate, lungs, thymus, kidney and colon [5,6], plasma membrane expression of functional protein was found in liver cells only [5–8]. Adjacent hepatocytes form tight junctions to enclose functional structures called bile canaliculi, to which BSEP is targeted. Bile salts undergo an enterohepatic circulation, which depends on active transport systems in the liver and intestine. In the course of this process, newly synthesized and recycled bile salts are secreted from hepatocytes into bile canaliculi by BSEP and via bile ducts reach the duodenum. In the ileum, these bile salts are reabsorbed by the apical sodium-dependent bile salt transporter in intestinal epithelial cells (ASBT/SLC10A2). From the intestine, bile salts return to the liver via the superior mesenteric and portal veins, which carry the blood that feeds liver sinusoids. Uptake into hepatocytes is mediated by the sodium taurocholate co-transporting polypeptide (NTCP/SLC10A1) and organic anion transporters (OATPs). Bile salt transport by BSEP constitutes the rate-limiting step in bile formation and provides the major driving force for enterohepatic circulation [9].

– The bile salt pool is recycled from the intestine to the liver six to eight times a day [10], resulting in daily bile salt excretion of about 20–40 g [11]. Impairment of BSEP results in the failure to maintain physiological bile flow, resulting in a clinical condition called intrahepatic cholestasis. BSEP has narrow specificity for its substrate bile salts, but the drugs pravastatin, vinblastine and fexofenadine are reported to be nonphysiological substrates [12–14].

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