Tauroursodesoxycholate-induced choleresis involves p38(MAPK) activation and translocation of the bile salt export pump in rats.
OBJECTIVE
Canalicular secretion of bile acids is stimulated by tauroursodesoxycholate (TUDC). This study investigates the underlying mechanisms.


METHODS
TUDC effects on mitogen-activated protein (MAP) kinases, taurocholate (TC) excretion, proteolysis, and the localization of the bile salt export pump (Bsep) were studied in rat hepatocytes and perfused liver.


RESULTS
TUDC induced a transient and concentration-dependent activation of p38(MAPK) and of extracellular signal-regulated kinase 2 (Erk-2), but not of c-Jun-N-terminal kinase (JNK). In perfused liver, TUDC concentrations of 20 micromol/L was sufficient to elicit the MAP kinase responses and TC choleresis. SB 202190, a specific inhibitor of p38(MAPK), had no effect on TUDC- induced Erk activation but abolished the stimulatory effect of TUDC on TC excretion in perfused liver, indicating the requirement of p38(MAPK) in addition to the reported Erk dependence for the choleretic response. TUDC-induced stimulation of TC excretion was accompanied by a p38(MAPK)-dependent insertion of subcanalicular immunoreactive Bsep into the canalicular membrane. In addition TUDC induced a p38(MAPK)-sensitive inhibition of proteolysis.


CONCLUSIONS
TUDC-induced stimulation of canalicular TC excretion involves a MAP kinase-dependent translocation of subcanalicular Bsep to the canalicular membrane. Dual activation of Erks and p38(MAPK) is required for the choleretic effect of both TUDC and hypo-osmotic cell swelling.
Kurz
A K
AK
Department of Gastroenterology, Hepatology and Infectiology, Medizinische Einrichtungen der Heinrich-Heine Universität Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany.
Graf
D
D
Schmitt
M
M
Vom Dahl
S
S
Häussinger
D
D
D000818:Animals; D002478:Cells, Cultured; D002756:Cholagogues and Choleretics / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D007093:Imidazoles / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000201:enzymology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009994:Osmolar Concentration; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*; D013656:Taurocholic Acid / Q000493:pharmacokinetics*; D048051:p38 Mitogen-Activated Protein Kinases
D002756:Cholagogues and Choleretics; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D013655:Taurochenodeoxycholic Acid; D013656:Taurocholic Acid; C031655:ursodoxicoltaurine; D019950:Mitogen-Activated Protein Kinase 1; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole