Impact of genetic and non-genetic factors on hepatic CYP2C9 expression and activity in Hungarian subjects.

Autor: Fekete F; Institute of Enzymology, Research Centre for Natural Sciences, Magyar tudósok 2, Budapest, 1117, Hungary., Mangó K; Institute of Enzymology, Research Centre for Natural Sciences, Magyar tudósok 2, Budapest, 1117, Hungary., Déri M; Institute of Enzymology, Research Centre for Natural Sciences, Magyar tudósok 2, Budapest, 1117, Hungary., Incze E; Institute of Enzymology, Research Centre for Natural Sciences, Magyar tudósok 2, Budapest, 1117, Hungary., Minus A; Institute of Enzymology, Research Centre for Natural Sciences, Magyar tudósok 2, Budapest, 1117, Hungary., Monostory K; Institute of Enzymology, Research Centre for Natural Sciences, Magyar tudósok 2, Budapest, 1117, Hungary. monostory.katalin@ttk.hu.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2021 Aug 24; Vol. 11 (1), pp. 17081. Date of Electronic Publication: 2021 Aug 24.
DOI: 10.1038/s41598-021-96590-3
Abstrakt: 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.
(© 2021. The Author(s).)
Databáze: MEDLINE
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