Bile Formation

Bile formation is an osmotic secretory process that is driven by the active concentration of bile salts in the bile canaliculi. Various transport mechanisms in the basolateral (sinusoidal) and apical (canalicular) surfaces of the hepatocytes facilitate this active concentration. The rate limiting step in this process is via transport across the canalicular membrane side of the hepatocyte.

Within the sinusoidal membrane, Na/K ATPase maintains a –35mV charge which drives several transport mechanisms. The Na/H+ pump drives protons out of the cell whilst HCO3- is exhanged for Na+ facilitating the entry of bicarbonate. Therefore active concentration of bile salts or acids is Na+ dependent and transport from the plasma into hepatocytes is mediated by the sodium taurocholate cotransporter.Other non-conjugated bile salt (cholate) and lipophilic albimin-bound compounds are transported from plasma into hepatocytes via a sodium-independent transporter. Bile salts are the most abundant solutes in bile

• • Canalicular membrane
    • Rate limiting step
    • Transport via ATP-dependent pumps (ATP-binding cassette family of membrane transporters)

E.g.: multidrug resistance-1 P-glycoprotein (MDR1) – mediates transport of bulky lipophilic cations (e.g.: anticancer drugs, cyclosporine A, etc).

• • • Physiological role – unclear, ?substrate

MDR3 – liver specific function cf: MDR1, it transports phosphatidylcholine from the inner to the outer leaflet of the canalicular membrane.

• • • Canalicular multispecific organic-anion transporter – a canalicular form of the multidrug resistance-associated protein (MDP2) – mediates transport of leukotriene C4, glutathione-S conjugates, glucuronides (bilirubin diglucuronide, estrodiol-17β- glucuronide) largely responsible for generation of bile flow independent of bile salts within the bile canaliculi.
    • Canalicular bile salt transporter – probably a member of the ATPase binding cassette family.

• Bile flow also affected by exocytosis of transcytotic and subcanalicular vesicles; activities of peptidases, nulceotidases, periodic contractions of bile canaliculi, bile ductule and hepatocyte ion channels, etc.
• Chloride is excreted by the chloride/bicarbonate anion exchanger and the cystic fibrosis transmembrane regulator (CFTR) (Cl- channel on the luminal surface of the bile duct epithelial cells).