ABC Transporters, Organic Solute Carriers and Drug Metabolising Enzymes in Bile Duct Epithelial Cells
The sodium-dependent bile salt transporter ASBT in the apical domain of cholangiocytes allows the reabsorption of bile salts in intrahepatic bile ducts. MRP3, a transporter of glucuronide-conjugates and of bile salts, and t-ASBT, a truncated form of ASBT, are expressed in the basolateral domain of the surface membrane of cholangiocytes and mediate the efflux of bile salts from cholangiocytes to the portal interstitial tissue and from there to the periductular capillary blood. NTCP, the sodium dependent transporter of bile salts, and BSEP, the bile salt export pump, are exclusively expressed in hepatocytes, not in cholangiocytes. Together these transporters enable the cholehepatic cycling of bile salts.
MRP1 and MDR1, like MRP3 are transporters belonging to the ATP-binding cassette family of proteins. They are also expressed in cholangiocytes. These transporters mediate the efflux of drugs and endogenous metabolites. In addition, cholangiocytes contain drug metabolising enzymes such as the cytochrome P-450 isoenzymes 2E1, 1A1, 1A2, 3A4 and 3A5, various UDP-glucuronosyltransferases, glutathione S-transferases and epoxide hydrolase. Thus, drugs that are reabsorbed from bile, may either be bioactivated or inactivated and transported out of the cholangiocyte. This suggests that cholangiocytes play a more active role in drug metabolism than hitherto recognized. Moreover, the cytochrome P-450 bioactivation of some drugs may explain drug-mediated toxicity directed at the bile ducts.
Functionally cholehepatic cycling of bile salts and drugs may contribute to generation of bile flow. The downside of this is that cholangiocytes are repeatedly exposed to potentially toxic drugs. Therefore cholangiocytes need to maintain their internal milieu within safe limits. As in hepatocytes this may be achieved by transcriptional and post-translational control mechanisms affecting the expression of enzymes and transporters. However, in cholangiocytes this needs to be studied. In addition, cholehepatic cycling of bile salts may contribute to gallstone formation. At the level of hepatocytes, bile salts enable the solubilisation of cholesterol. Subsequent reabsorption of bile salts in the intrahepatic bile ducts may then lead to cholesterol precipitation and gallstone formation. Therefore, candidate genes for gallstone formation, the so-called Lith genes, may turn out to be transporter-genes or their regulators.