ArticlePloS one2012
ERK1/2 and p38 MAPKs are complementarily involved in estradiol 17ß-D-glucuronide-induced cholestasis: crosstalk with cPKC and PI3K.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 30 citations in OpenAlex.
- Regulation of ABC transporters by sex steroids may explain differences in drug resistance between sexes.Journal of physiology and biochemistry · 2023Review
- The Bile Salt Export Pump: Molecular Structure, Study Models and Small-Molecule Drugs for the Treatment of Inherited BSEP Deficiencies.International journal of molecular sciences · 2021Review
- The Pathological Mechanisms of Estrogen-Induced Cholestasis: Current Perspectives.Frontiers in pharmacology · 2021Review
- Abnormal Expression of ERα in Cholangiocytes of Patients With Primary Biliary Cholangitis Mediated Intrahepatic Bile Duct Inflammation.Frontiers in immunology · 2019Article
- p38 MAPK α and β isoforms differentially regulate plasma membrane localization of MRP2.American journal of physiology. Gastrointestinal and liver physiology · 2016Article
- Different dose-dependent mechanisms are involved in early cyclosporine a-induced cholestatic effects in hepaRG cells.Toxicological sciences : an official journal of the Society of Toxicology · 2014Article
- Calcitonin Gene-Related Peptide Regulates Cardiomyocyte Survival through Regulation of Oxidative Stress by PI3K/Akt and MAPK Signaling Pathways.Annals of clinical and experimental hypertension · 2014Article
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
objectiveThe endogenous, cholestatic metabolite estradiol 17ß-D-glucuronide (E(2)17G) induces endocytic internalization of the canalicular transporters relevant to bile formation, Bsep and Mrp2. We evaluated here whether MAPKs are involved in this effect.
designERK1/2, JNK1/2, and p38 MAPK activation was assessed by the increase in their phosphorylation status. Hepatocanalicular function was evaluated in isolated rat hepatocyte couplets (IRHCs) by quantifying the apical secretion of fluorescent Bsep and Mrp2 substrates, and in isolated, perfused rat livers (IPRLs), using taurocholate and 2,4-dinitrophenyl-S-glutathione, respectively. Protein kinase participation in E(2)17G-induced secretory failure was assessed by co-administering selective inhibitors. Internalization of Bsep/Mrp2 was assessed by confocal microscopy and image analysis.
resultsE(2)17G activated all kinds of MAPKs. The PI3K inhibitor wortmannin prevented ERK1/2 activation, whereas the cPKC inhibitor Gö6976 prevented p38 activation, suggesting that ERK1/2 and p38 are downstream of PI3K and cPKC, respectively. The p38 inhibitor SB203580 and the ERK1/2 inhibitor PD98059, but not the JNK1/2 inhibitor SP600125, partially prevented E(2)17G-induced changes in transporter activity and localization in IRHCs. p38 and ERK1/2 co-inhibition resulted in additive protection, suggesting complementary involvement of these MAPKs. In IPRLs, E(2)17G induced endocytosis of canalicular transporters and a rapid and sustained decrease in bile flow and biliary excretion of Bsep/Mrp2 substrates. p38 inhibition prevented this initial decay, and the internalization of Bsep/Mrp2. Contrarily, ERK1/2 inhibition accelerated the recovery of biliary secretion and the canalicular reinsertion of Bsep/Mrp2.
conclusionscPKC/p38 MAPK and PI3K/ERK1/2 signalling pathways participate complementarily in E(2)17G-induced cholestasis, through internalization and sustained intracellular retention of canalicular transporters, respectively.
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