Canalicular bile

A. F., Meier, P. J., The sister ofP-glycoprotein represents the canalicular bile salt export pump of mammalian liver, J. Biol. Chem. 1998, 273, 10046-10050. 

Funk, C., Ponelle, C., Scheuermann, G., Pantze, M., Cholestatic potential of troglitazone as a possible factor contributing to troglitazone-induced hepatotoxicity in vivo and in vitro interaction at the canalicular bile salt export pump (Bsep) in the rat, Mol. Pharmacol. 2001, 59, 627-635. 

Bolder U, Trang NV, Hagey LR, Schteingart CD, Ton-Nu HT, Cerre C et al. Sulindac is excreted into bile by a canalicular bile salt pump and undergoes a cholehepatic circulation in rats. Gastroenterology 1999 117(4) 962—971. 

Funk, C. et al. (2001) Troglitazone-induced intrahepatic cholestasis by an interference with the hepatobiliary export ofbile acids in male and female rats. Correlation with the gender difference in troglitazone sulfate formation and ihe inhibition of the canalicular bile salt export pump (Bsep) by troglitazone and troglitazone sulfate. Toxicology, 167 (1), 83-98. 

Primary bile, already containing various compounds (= solutes) collected during transcellular transport, is formed by osmotic filtration at the canalicular membrane of the hepatocytes. It is yellow to orange in colour. Para-cellular incorporation of further solutes into the bile occurs via the intercellular gap and the tight junctions. The canalicular bile flow comprises two fractions ... 

The bile acid uptake capacity at the sinusoidal membrane is 8-10 times higher than the secretion rate at the canalicular membrane. Approximately 450 ml canalicular bile are formed daily, each fraction constituting half of this total. Secretion of bile into the canaliculi is further assisted by microfilaments. In the case of loss of microfilament function, the canaliculi become broadened and immobile, thereby also inhibiting the bile flow. 

PFIC 2 This gene mutation, which is located on chromosome 2q24, impairs the canalicular bile salt export pump (BSEP), resulting in the accumulation of bile acids in hepatocytes. Laboratory tests show an increase in bile acid, AP and LAP levels with lowered gamma GT and cholesterol levels. Pruritus is common. There is histological evidence of neonatal giant cell hepatitis. Prognosis is poor. 

The endothelin antagonist bosentan inhibits the canalicular bile salt export pump a potential mechanism for hepatic adverse reactions. Clinical Pharmacology and Therapeutics, 69, 223-231. 

Biliary excretion of contrast medium is affected by the bile flow (688, 734, 745, 777, 778). Bile is isosmotic with plasma and is produced from the transport of water from the liver cell into the bile canaliculi (canalicular bile flow) and from the excretion and reabsorption of water and electrolytes in the bile ductules (ductular bile flow). Bile flow is increased by taurocholate and dehydrocholate their presence in the canaliculi creates an osmotic gradient that produces the flow of water and solute. There is a positive correlation between the canalicular bile flow stimulated by taurocholate and the amount of iopanoic acid excreted by the liver. Feeding the patient a fatty meal or taurocholate at the time that iopanoic acid is administered can improve the quality of cholecystograms(734). 

Noe, J., Stieger. B., and Meier, P.J. (2002) Functional expression of the canalicular bile salt export pump ofhuman liver. Gastroenterology, 123 (5), 1659—1666. 

Until recently, it was considered that hepatic bile flow was still possible even if no bile acids were excreted. This portion of bile flow was termed bile acid independent and was estimated to account for around one-third of canalicular bile flow in man (B33, P15). More recent evidence suggests that the relationship between bile flow and bile acid excretion is curvilinear, so that bile flow decreases progressively more rapidly as bile acid excretion rates decrease to very low values (B2, B24). Bile-salt-independent bile flow may therefore be much lower than previously thought and represent only a very small fraction of total bile flow (B24). 

B2. Baker, A. L., and Wood, R. A. B., Moosa, A. R., and Boyer, J. L., Sodium taurocholate modifies the bile acid-independent fraction of canalicular bile flow in the rhesus monkey. /. Clin. Invest. 64, 312-320 (1979). 

B33. Boyer, J. L., and Bloomer, J. R., Canalicular bile secretion in man Studies utilizing the biliary clearance of i -mannitol. J. Clin. Invest. 54, 773-781 (1974). 

Troglitazone sulfate (Ml, the main metabolite) undergoes biliary excretion and accounts for up to 85% of the dose in humans (Loi et al. 1999). In patients with hepatic impairment, troglitazone sulfate was found to accumulate about fourfold in plasma with a threefold increased half-life (Ott et al. 1998 Loi et al. 1999). This metabolite also inhibited the canalicular bile salt export pump (Bsep), organic anion transporting polypeptide (OATP) transporters as well as drug transporters, suggesting it contributes to the hepatotoxicity. 

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