ArticleThe Journal of biological chemistry2014
Altered expression of small heterodimer partner governs cytochrome P450 (CYP) 2D6 induction during pregnancy in CYP2D6-humanized mice.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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The trial behind it
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Who cites it
31 citing papers in PubMed, 52 citations in OpenAlex.
- Impact of Pregnancy and Vitamin A Supplementation on CYP2D6 Activity.Journal of clinical pharmacology · 2023Trial
- Does In Vitro Cytochrome P450 Downregulation Translate to In Vivo Drug-Drug Interactions? Preclinical and Clinical Studies With 13-cis-Retinoic Acid.Clinical and translational science · 2019Trial
- Pharmacokinetics of metoprolol during pregnancy and lactation.Journal of clinical pharmacology · 2016Trial
- Effect of isotretinoin on CYP2D6 and CYP3A activity in patients with severe acne.British journal of clinical pharmacology · 2024Article
- Novel Independent Trans- and Cis-Genetic Variants Associated with CYP2D6 Expression and Activity in Human Livers.Drug metabolism and disposition: the biological fate of chemicals · 2024Article
- CYP2D6 Activity Is Correlated with Changes in Plasma Concentrations of Taurocholic Acid during Pregnancy and Postpartum in CYP2D6 Extensive Metabolizers.Drug metabolism and disposition: the biological fate of chemicals · 2023Article
- A longitudinal study of cytochrome P450 2D6 (CYP2D6) activity during adolescence.Clinical and translational science · 2022Article
- Isotretinoin and its Metabolites Alter mRNA of Multiple Enzyme and Transporter Genes In Vitro, but Downregulation of Organic Anion Transporting Polypeptide Does Not Translate to the Clinic.Drug metabolism and disposition: the biological fate of chemicals · 2022Article
- A Review of the Important Role ofGenes · 2020Review
- Methods to study mechanisms underlying altered hepatic drug elimination during pregnancy.Seminars in perinatology · 2020Review
- Physiologically-Based Pharmacokinetic Modeling for the Prediction of CYP2D6-Mediated Gene-Drug-Drug Interactions.CPT: pharmacometrics & systems pharmacology · 2019Article
- Determinants of Cytochrome P450 2D6 mRNA Levels in Healthy Human Liver Tissue.Clinical and translational science · 2019Article
- P450-Humanized and Human Liver Chimeric Mouse Models for Studying Xenobiotic Metabolism and Toxicity.Drug metabolism and disposition: the biological fate of chemicals · 2018Review
- CYP2D6 Protein Level Is the Major Contributor to Interindividual Variability in CYP2D6-Mediated Drug Metabolism in Healthy Human Liver Tissue.Clinical pharmacology and therapeutics · 2018Article
- Physiological Regulation of Drug Metabolism and Transport: Pregnancy, Microbiome, Inflammation, Infection, and Fasting.Drug metabolism and disposition: the biological fate of chemicals · 2018Article
- Ten Years' Experience with the CYP2D6 Activity Score: A Perspective on Future Investigations to Improve Clinical Predictions for Precision Therapeutics.Journal of personalized medicine · 2018Review
- Inhibition of theDrug metabolism and disposition: the biological fate of chemicals · 2017Article
- High-Fat Diet Feeding Alters Expression of Hepatic Drug-Metabolizing Enzymes in Mice.Drug metabolism and disposition: the biological fate of chemicals · 2017Article
- Cholic Acid Feeding Leads to Increased CYP2D6 Expression in CYP2D6-Humanized Mice.Drug metabolism and disposition: the biological fate of chemicals · 2017Article
- Transcriptional Regulation of CYP2D6 Expression.Drug metabolism and disposition: the biological fate of chemicals · 2017Review
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Authors and funding
8 authors at 5 institutions in 1 country.
Funding
Abstract
Substrates of a major drug-metabolizing enzyme CYP2D6 display increased elimination during pregnancy, but the underlying mechanisms are unknown in part due to a lack of experimental models. Here, we introduce CYP2D6-humanized (Tg-CYP2D6) mice as an animal model where hepatic CYP2D6 expression is increased during pregnancy. In the mouse livers, expression of a known positive regulator of CYP2D6, hepatocyte nuclear factor 4α (HNF4α), did not change during pregnancy. However, HNF4α recruitment to CYP2D6 promoter increased at term pregnancy, accompanied by repressed expression of small heterodimer partner (SHP). In HepG2 cells, SHP repressed HNF4α transactivation of CYP2D6 promoter. In transgenic (Tg)-CYP2D6 mice, SHP knockdown led to a significant increase in CYP2D6 expression. Retinoic acid, an endogenous compound that induces SHP, exhibited decreased hepatic levels during pregnancy in Tg-CYP2D6 mice. Administration of all-trans-retinoic acid led to a significant decrease in the expression and activity of hepatic CYP2D6 in Tg-CYP2D6 mice. This study provides key insights into mechanisms underlying altered CYP2D6-mediated drug metabolism during pregnancy, laying a foundation for improved drug therapy in pregnant women.
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Registered trials
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.