Partial characterization of cytoprotective mechanisms of lecithin against bile salt-induced bile duct damage.

Background: We recently demonstrated that cyclosporine A causes a disproportionate reduction of biliary lipid secretion, and this is inhibited by hydrophilic bile salts through the enhancing of biliary lecithin secretion. In the present study, the underlying mechanism of such a cytoprotective action of hydrophilic bile salts was determined with attention to the possible role of lecithin.

Methods: Immortalized mouse cholangiocytes were cultured for 4 h with taurine conjugates of a hydrophobic bile salt (cholate [TC]), and hydrophilic bile salts (ursodeoxycholate [TUDC], betamuricholate [TbetaMC], and alphamuricholate [TalphaMC]), at 200 microM, in the presence or absence of lecithin (5, 10, 25, 50, 100, or 200 microM), followed by flow cytometric detection of apoptosis, using Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining. Cholangiocyte bile salt transporter mRNAs (apical sodium-dependent bile-salt transporter [Asbt] and multidrug resistance protein 3 [Mrp3]) were determined by reverse transcription-polymerase chain reaction (RT-PCR).

Results: Apoptosis was induced by all of the bile salts (TC > TUDC, TbetaMC, and TalphaMC). Interestingly, bile salt-induced apoptosis was inhibited by lecithin in a concentration-dependent manner. Further, RT-PCR showed that the expressions of Asbt and Mrp3 mRNAs were enhanced by all the bile salts, whereas lecithin reduced Asbt expression, but enhanced Mrp3 expression.

Conclusions: These findings indicate that bile salts cause bile-duct cell damage through Asbt-mediated uptake, but that biliary lecithin physiologically inhibits such damage by reducing the expression of this transporter. In addition, the induction of Mrp3 expression by lecithin may play a role in inhibiting the accumulation of bile. Thus, the modulation of lecithin secretion into bile may be another important target for the treatment of biliary disorders.