Review article: new insights into the mechanisms of hepatic transport and bile secretion.

The transport processes responsible for bile flow are reviewed. Canalicular bile acid-dependent flow is the result of active transport of bile acids by the hepatocyte into bile canaliculi. Bile acids are taken up by at least two transport systems whose mRNA have been expressed in Xenopus oocytes: (i) a Na(+)-dependent system, named NTCP, and (ii) a Na(+)- independent system, named OATP. Bile acids are then secreted into bile by two other transport systems, an ATP-dependent system and an 'electrogenic' voltage-dependent system. It is not known whether these two systems are mediated by the same protein or by two different proteins. Canalicular bile acid-independent flow is mainly the result of the secretion of glutathione into bile. The canalicular membrane also contains several proteins of the multi drug resistance (MDR) family. MDRI is responsible for biliary secretion of cationic drugs. MDR3 (mdr 2 in mice) plays a major role in the secretion of phospholipids. A third MDR-related protein has been shown recently to be the canalicular carrier of organic anions, such as bilirubin and dyes (the canalicular multiple organic anion transporter, or cMOAT). Biliary epithelial cells secrete a bicarbonate-rich solution, mostly in response to secretin. This secretion depends upon the presence, on the apical membrane of these cells of the CFTR, a chloride channel activated by cAMP and of a chloride/bicarbonate exchanger. Knowledge of these transport systems should allow a better understanding of the mechanisms involved in cholestasis.