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Impact of physiological, pathological and environmental factors on the expression and activity of human cytochrome P450 2D6 and implications in precision medicine
- Source :
- Drug Metabolism Reviews. 47:470-519
- Publication Year :
- 2015
- Publisher :
- Informa UK Limited, 2015.
-
Abstract
- With only 1.3-4.3% in total hepatic CYP content, human CYP2D6 can metabolize more than 160 drugs. It is a highly polymorphic enzyme and subject to marked inhibition by a number of drugs, causing a large interindividual variability in drug clearance and drug response and drug-drug interactions. The expression and activity of CYP2D6 are regulated by a number of physiological, pathological and environmental factors at transcriptional, post-transcriptional, translational and epigenetic levels. DNA hypermethylation and histone modifications can repress the expression of CYP2D6. Hepatocyte nuclear factor-4α binds to a directly repeated element in the promoter of CYP2D6 and thus regulates the expression of CYP2D6. Small heterodimer partner represses hepatocyte nuclear factor-4α-mediated transactivation of CYP2D6. GW4064, a farnesoid X receptor agonist, decreases hepatic CYP2D6 expression and activity while increasing small heterodimer partner expression and its recruitment to the CYP2D6 promoter. The genotypes are key determinants of interindividual variability in CYP2D6 expression and activity. Recent genome-wide association studies have identified a large number of genes that can regulate CYP2D6. Pregnancy induces CYP2D6 via unknown mechanisms. Renal or liver diseases, smoking and alcohol use have minor to moderate effects only on CYP2D6 activity. Unlike CYP1 and 3 and other CYP2 members, CYP2D6 is resistant to typical inducers such as rifampin, phenobarbital and dexamethasone. Post-translational modifications such as phosphorylation of CYP2D6 Ser135 have been observed, but the functional impact is unknown. Further functional and validation studies are needed to clarify the role of nuclear receptors, epigenetic factors and other factors in the regulation of CYP2D6.
- Subjects :
- Epigenomics
medicine.medical_specialty
Receptors, Cytoplasmic and Nuclear
digestive system
Gene Expression Regulation, Enzymologic
Substrate Specificity
Arthritis, Rheumatoid
Transactivation
Alzheimer Disease
Liver Cirrhosis, Alcoholic
Internal medicine
Diabetes Mellitus
medicine
Animals
Humans
Pharmacology (medical)
Epigenetics
Precision Medicine
General Pharmacology, Toxicology and Pharmaceutics
skin and connective tissue diseases
Inflammation
Polymorphism, Genetic
biology
Liver Diseases
Parkinson Disease
Cell biology
Endocrinology
Histone
Cytochrome P-450 CYP2D6
Hepatocyte Nuclear Factor 4
Nuclear receptor
Hepatocyte nuclear factor 4
biology.protein
Small heterodimer partner
Kidney Failure, Chronic
Farnesoid X receptor
Plant Preparations
Protein Processing, Post-Translational
Genome-Wide Association Study
Subjects
Details
- ISSN :
- 10979883 and 03602532
- Volume :
- 47
- Database :
- OpenAIRE
- Journal :
- Drug Metabolism Reviews
- Accession number :
- edsair.doi.dedup.....d9cd2cc9695ebc83dba3267a9a1a9349