Hepatic Bile Formation: Developing a New Paradigm

Pharmacol Rev. 2023 Aug 2:PHARMREV-AR-2022-000799. doi: 10.1124/pharmrev.122.000799. Online ahead of print.ABSTRACTIn 1959, Ivar Sperber contrasted bile formation with that of urine and proposed that water flow into the canalicular conduit is in response to an osmotic not a hydrostatic gradient. Early attempts to support the hypothesis using a bile acid, sodium taurocholate, and the hormone secretin to stimulate bile flow led to conflicting data and a moratorium on attempts to further develop the initial proposal. However, current data amplifiy the proposal and indicate both paracellular and transcellular water flow into hepatic ductules and the canalicular conduit in response to an osmotic gradient. Also, the need to further modify the initial proposal became apparent with the recognition that bile acid aggregates (micelles) generate lecithin-cholesterol vesicles that contain water unrelated to an osmotic gradient. As part of this development is the recent introduction of the FLAP technique for direct determination of hepatic duct flow and clarification of the role of biomarkers such as mannitol and polyethylene glycol 900. With the new paradigm these biomarkers may prove useful for quantifying paracellular and transcellular water flow, respectively.Significance Statement It is essential to identify and characterize all the sites for water flow during hepatic bile formation to obtain more precision in evaluating the causes and possible therapeutic approaches to cholestatic s...
Source: Pharmacological Reviews - Category: Drugs & Pharmacology Authors: Source Type: research