Combination of CYP2C19 genotype with non-genetic factors evoking phenoconversion improves phenotype prediction

Background: CYP2C19 is an important drug-metabolizing enzyme, responsible for metabolism of approximately 10% of the drugs on the market. Large inter-individual differences exist in metabolic activities, which are primarily attributed to genetic polymorphism of CYP2C19 gene. Conflicting results have been published about the role of CYP2C19 polymorphisms in metabolism of CYP2C19 substrates and clinical outcomes; thus, we aimed to investigate CYP2C19 genotype-phenotype associations, and we sought to elicit potential causes of discrepancies in the genotype-based prediction by incorporating the liver donors' demographic data, drug administration events and pathological conditions. Methods: (S)-Mephenytoin was used to assess CYP2C19 activities in human liver microsomes derived from 114 Hungarian organ donors. CYP2C19 genotype was determined by SNP genotyping for CYP2C19* 2, CYP2C19* 3, CYP2C19* 4 and CYP2C19* 17 variants, and CYP2C19 mRNA levels were measured by qPCR method. Clinical data of the donors were considered in the genotype-based phenotype prediction. Results: CYP2C19 phenotype of 40% of the donors was well-predicted from the genotype data, whereas the phenotype of 13% was underestimated displaying higher activity, and of 47% was overestimated displaying lower activity than predicted from CYP2C19 genotype. Among the donors with overestimated phenotype, one was treated with CYP2C19 substrate/inhibitor, 9 were on amoxicillin-clavulanic acid therapy, 7 were chronic alcohol consumers and 9 had disease with inflammatory processes. Conclusions: CYP2C19 genotype only partially determines the CYP2C19 phenotypic appearance; comedication, diseases with inflammatory processes and aspecific factors, such as chronic alcohol consumption and amoxicillin-clavulanic acid therapy (or any drug therapy resulting in liver injury) seem to be potential phenotype-modifying factors. (c) 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.