Coordinate transcriptional regulation of bile acid homeostasis and drug metabolism

Eloranta, Jyrki J.; Kullak-Ublick, Gerd A.

doi:10.1016/j.abb.2004.09.019

Cited by 263Drug Transport and Resistance MechanismsPharmacogenetics and Drug MetabolismCholesterol and Lipid Metabolism

Coordinate transcriptional regulation of bile acid homeostasis and drug metabolism

Eloranta, Jyrki J., Kullak-Ublick, Gerd A.·2005·Archives of Biochemistry and Biophysics

DOI 10.1016/j.abb.2004.09.019

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Abstract

Drugs and bile acids are taken up into hepatocytes by specialized transport proteins localized at the basolateral membrane, e.g., organic anion transporting polypeptides . Following intracellular metabolism by cytochrome P450 (CYP) enzymes, drug metabolites are excreted into bile or urine via ATP-dependent multidrug resistance proteins (MDR1 and MRPs). Bile acids are excreted mainly via the bile salt export pump (BSEP, ABCB11). The genes coding for drug and bile acid transporters and CYP enzymes are regulated by a complex network of transcriptional cascades, notably by the ligand-activated nuclear receptors FXR, PXR, and CAR and by the ligand-independent nuclear receptor HNF-4alpha. The bile acid synthesizing enzymes CYP7A1, CYP8B1, and CYP27A1 are subject to negative feedback regulation by bile acids, which is partly mediated through the transcriptional repressor SHP. The role of transcriptional cofactors, such as SRC-1 and PGC-1, in mediating the gene-specific effects of individual nuclear receptors is becoming increasingly evident.

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Authors: Eloranta, J. J., & Kullak-Ublick, G. A.
Affiliations: University Hospital Zurich (CH)
Corresponding author: Kullak-Ublick, Gerd A.
ORCID: Kullak-Ublick, Gerd A.
Venue: Archives of Biochemistry and Biophysics
Publisher: Elsevier BV
Published: 2005-01
Volume: 433
Issue: 2
Pages: 397-412
ISSN: 0003-9861 (ISSN-L)
DOI: 10.1016/j.abb.2004.09.019
OpenAlex: W1978400865
Semantic Scholar: c6f22fe2f538c31b7bfd9346d8cc625e99d3b177
Cited by: 260
References: 173
Citations by year: 2026: 4 · 2025: 3 · 2024: 5 · 2023: 4 · 2022: 5 · 2021: 5 · 2020: 22 · 2019: 5 · 2018: 6 · 2017: 5 · 2016: 8 · 2015: 6 · 2014: 11 · 2013: 16 · 2012: 10
FWCI: 2.69
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Archives of Biochemistry and Biophysics (publishedVersion)
PubMed (publishedVersion)
Funders: Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
Topics: Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords: bile acid homeostasis, drug metabolism, hepatocytes, transcriptional regulation, nuclear receptors, farnesoid X receptor, pregnane X receptor, HNF4α, organic anion transporting polypeptides, multidrug resistance protein, bile salt export pump, ABCB11, CYP enzymes, CYP7A1, CYP8B1, CYP27A1, SHP, negative feedback regulation, transcriptional cofactors, PGC-1, SRC-1, bile acid transporters
MeSH terms: Pregnane X Receptor, Receptor, Farnesoid X-Activated, Animals, Bile Acids and Salts, Cholesterol 7-alpha-Hydroxylase, Cytochrome P-450 Enzyme System, DNA-Binding Proteins, Pharmaceutical Preparations, Forecasting, Heat-Shock Proteins, Homeostasis, Humans, Ligands, Models, Biological, Phosphoproteins, Receptors, Glucocorticoid, Receptors, Steroid, Receptors, Virus, Steroid Hydroxylases, Steroid 12-alpha-Hydroxylase, Transcription Factors, Transcription, Genetic, Trans-Activators, Receptors, Cytoplasmic and Nuclear, Receptors, Calcitriol, Feedback, Physiological, ATP-Binding Cassette, Sub-Family C Proteins, Histone Acetyltransferases, Hepatocyte Nuclear Factor 4, Cholestanetriol 26-Monooxygenase, Nuclear Receptor Coactivator 1, Coxsackie and Adenovirus Receptor-Like Membrane Protein

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Coordinate transcriptional regulation of bile acid homeostasis and drug metabolism

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