ArticleDrug metabolism and disposition: the biological fate of chemicals2013
p38 Mitogen-activated protein kinase regulates nuclear receptor CAR that activates the CYP2B6 gene.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 21 citations in OpenAlex.
- Human Orphan Cytochromes P450: An Update.Current drug metabolism · 2022Article
- The role of pregnane X receptor (PXR) in substance metabolism.Frontiers in endocrinology · 2022Review
- Constitutive androstane receptor regulates the intestinal mucosal response to injury.British journal of pharmacology · 2017Article
- Phenobarbital Meets Phosphorylation of Nuclear Receptors.Drug metabolism and disposition: the biological fate of chemicals · 2017Article
- p38 MAP Kinase Links CAR Activation and Inactivation in the Nucleus via Phosphorylation at Threonine 38.Drug metabolism and disposition: the biological fate of chemicals · 2016Article
- Transactivation Assays to Assess Canine and Rodent Pregnane X Receptor (PXR) and Constitutive Androstane Receptor (CAR) Activation.PloS one · 2016Article
- Deciphering the roles of the constitutive androstane receptor in energy metabolism.Acta pharmacologica Sinica · 2015Review
- Metformin represses drug-induced expression of CYP2B6 by modulating the constitutive androstane receptor signaling.Molecular pharmacology · 2014Article
- Signaling control of the constitutive androstane receptor (CAR).Protein & cell · 2014Review
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
The constitutive active/androstane receptor (CAR) regulates hepatic drug metabolism by activating genes, such as cytochrome P450, and certain transferases. p38 Mitogen-activated protein kinase (MAPK) is highly activated in human primary hepatocytes but barely in human hepatoma cell lines including HepG2 cells. Liganded-CAR induced CYP2B6 mRNA in human primary hepatocytes far more effectively than in HepG2 cells ectopically expressing CAR. In the present study, we found that activation of p38 MAPK by anisomycin potentiated induction of CYP2B6 mRNA by CAR ligand in HepG2 cells to levels observed in ligand-treated human primary hepatocytes. siRNA knockdown of p38 MAPK abrogated the ability of anisomycin to synergistically induce CYP2B6 mRNA. In addition to CYP2B6, anisomycin cotreatment potentiated an increase in CYP2A7 and CYP2C9 mRNAs but not CYP3A4 or UDP-glucuronosyltransferase 1A1 mRNAs. Thus, activated p38 MAPK is required for liganded-CAR to selectively activate a set of genes that encode drug-metabolizing enzymes. Our present results suggest that CAR-mediated induction of these enzymes cannot be understood by ligand binding alone because the specificity and magnitude of induction are codetermined by a given cell signaling, such as p38 MAPK; both physiologic and pathophysiological states of cell signaling may have a strong impact in hepatic drug-metabolizing capability during treatments.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.