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

Ferenc Fekete,Evelyn Incze,Annamária Minus,Katalin Monostory,Máté Déri,Katalin Mangó

doi:10.1038/s41598-021-96590-3

Ferenc Fekete, Evelyn Incze + Show 4 more

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https://doi.org/10.1038/s41598-021-96590-3

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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.

Highlights

CYP2C9, one of the most abundant hepatic cytochrome P450 enzymes, is involved in metabolism of 15–20% of clinically important drugs
The single nucleotide polymorphisms (SNPs) in CYP2C9*2 and CYP2C8*3 alleles were in significant linkage (D’ 0.87; LOD 18.8) in tissue donors all belonging to the Caucasian population, whereas other SNP pairs were in linkage disequilibrium
CYP2C9 is in the focus of pharmacogenetic studies for genotype-based drug therapy, because it is one of the most abundant hepatic CYP enzymes and catalyses the metabolism of many clinically important drugs, of those with narrow therapeutic concentration r ange[4,5,35]

Summary

Introduction

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). CYP2C9 is involved in the metabolism of approximately 15–20% of clinically used drugs, such as anticoagulants (S-acenocoumarol, S-warfarin), antiepileptics (phenytoin, valproate), non-steroid anti-inflammatory drugs (diclofenac, ibuprofen, flurbiprofen, celecoxib, valdecoxib), oral sulfonylurea antidiabetics (tolbutamide, glyburide), diuretics (torsemide, sulfinpyrazone), and antihypertensive angiotensin II receptor blockers (losartan, irbesartan)[2,3,4]. Many of these drugs, most prominently warfarin, acenocoumarol, sulfonylureas, valproate and phenytoin have a narrow therapeutic index; continuous monitoring of blood coagulation, serum glucose level and/or drug concentration is recommended. The association between CYP2C9 genotype and valproate blood concentrations was clearly demonstrated in children whose metabolic pathways of valproate other than CYP2C9-mediated routes are poorly developed, the impact of CYP2C9 genetic variability on valproate clearance was not significant in adult p atients[20]

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