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Impact of genetic and non-genetic factors on hepatic CYP2C9 expression and activity in Hungarian subjects
- Source :
- Scientific Reports, Vol 11, Iss 1, Pp 1-12 (2021), Scientific Reports
- Publication Year :
- 2021
- Publisher :
- Nature Portfolio, 2021.
-
Abstract
- CYP2C9, one of the most abundant hepatic cytochrome P450 enzymes, is involved in metabolism of 15–20% of clinically important drugs (warfarin, sulfonylureas, phenytoin, non-steroid anti-inflammatory drugs). To avoid adverse events and/or impaired drug-response, CYP2C9 pharmacogenetic testing is recommended. The impact of CYP2C9 polymorphic alleles (CYP2C9*2, CYP2C9*3) and phenoconverting non-genetic factors on CYP2C9 function and expression was investigated in liver tissues from Caucasian subjects (N = 164). The presence of CYP2C9*3 allele was associated with CYP2C9 functional impairment, and CYP2C9*2 influenced tolbutamide 4′-hydroxylase activity only in subjects with two polymorphic alleles, whereas the contribution of CYP2C8*3 was not confirmed. In addition to CYP2C9 genetic polymorphisms, non-genetic factors (co-medication with CYP2C9-specific inhibitors/inducers and non-specific factors including amoxicillin + clavulanic acid therapy or chronic alcohol consumption) contributed to the prediction of hepatic CYP2C9 activity; however, a CYP2C9 genotype–phenotype mismatch still existed in 32.6% of the subjects. Substantial variability in CYP2C9 mRNA levels, irrespective of CYP2C9 genotype, was demonstrated; however, CYP2C9 induction and non-specific non-genetic factors potentially resulting in liver injury appeared to modify CYP2C9 expression. In conclusion, complex implementation of CYP2C9 genotype and non-genetic factors for the most accurate estimation of hepatic CYP2C9 activity may improve efficiency and safety of medication with CYP2C9 substrate drugs in clinical practice.
- Subjects :
- Phenytoin
Adult
Male
medicine.medical_specialty
Alcohol Drinking
Science
Polymorphism, Single Nucleotide
Article
Medical research
Internal medicine
Genotype
medicine
Humans
Allele
CYP2C8
Adverse effect
CYP2C9
Clavulanic Acid
Aged
Cytochrome P-450 CYP2C9
Liver injury
Multidisciplinary
Molecular medicine
Ethanol
business.industry
Health care
Amoxicillin
Middle Aged
medicine.disease
Endocrinology
Biological Variation, Population
Liver
Medicine
Female
business
beta-Lactamase Inhibitors
Pharmacogenetics
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 20452322
- Volume :
- 11
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....b6fb1ef74b758168111093f088b7f77b