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

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 testin...

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Autores principales:	Ferenc Fekete, Katalin Mangó, Máté Déri, Evelyn Incze, Annamária Minus, Katalin Monostory
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b6e9c3ef1c064e07b6526c64bf166e4e
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spelling	oai:doaj.org-article:b6e9c3ef1c064e07b6526c64bf166e4e2021-12-02T16:34:54ZImpact of genetic and non-genetic factors on hepatic CYP2C9 expression and activity in Hungarian subjects10.1038/s41598-021-96590-32045-2322https://doaj.org/article/b6e9c3ef1c064e07b6526c64bf166e4e2021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-96590-3https://doaj.org/toc/2045-2322Abstract 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 (CYP2C92, CYP2C93) and phenoconverting non-genetic factors on CYP2C9 function and expression was investigated in liver tissues from Caucasian subjects (N = 164). The presence of CYP2C93 allele was associated with CYP2C9 functional impairment, and CYP2C92 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.Ferenc FeketeKatalin MangóMáté DériEvelyn InczeAnnamária MinusKatalin MonostoryNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ferenc Fekete Katalin Mangó Máté Déri Evelyn Incze Annamária Minus Katalin Monostory Impact of genetic and non-genetic factors on hepatic CYP2C9 expression and activity in Hungarian subjects
description	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 (CYP2C92, CYP2C93) and phenoconverting non-genetic factors on CYP2C9 function and expression was investigated in liver tissues from Caucasian subjects (N = 164). The presence of CYP2C93 allele was associated with CYP2C9 functional impairment, and CYP2C92 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.
format	article
author	Ferenc Fekete Katalin Mangó Máté Déri Evelyn Incze Annamária Minus Katalin Monostory
author_facet	Ferenc Fekete Katalin Mangó Máté Déri Evelyn Incze Annamária Minus Katalin Monostory
author_sort	Ferenc Fekete
title	Impact of genetic and non-genetic factors on hepatic CYP2C9 expression and activity in Hungarian subjects
title_short	Impact of genetic and non-genetic factors on hepatic CYP2C9 expression and activity in Hungarian subjects
title_full	Impact of genetic and non-genetic factors on hepatic CYP2C9 expression and activity in Hungarian subjects
title_fullStr	Impact of genetic and non-genetic factors on hepatic CYP2C9 expression and activity in Hungarian subjects
title_full_unstemmed	Impact of genetic and non-genetic factors on hepatic CYP2C9 expression and activity in Hungarian subjects
title_sort	impact of genetic and non-genetic factors on hepatic cyp2c9 expression and activity in hungarian subjects
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/b6e9c3ef1c064e07b6526c64bf166e4e
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Impact of genetic and non-genetic factors on hepatic CYP2C9 expression and activity in Hungarian subjects

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