Interindividual variability of CYP2C19-catalyzed drug metabolism due to differences in gene diplotypes and cytochrome P450 oxidoreductase content

Large interindividual variability has been observed in the metabolism of CYP2C19 substrates in vivo . The study aimed to evaluate sources of this variability in CYP2C19 activity, focusing on CYP2C19 diplotypes and the cytochrome P 450 oxidoreductase (POR). CYP2C19 gene analysis was carried out on 34...

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Veröffentlicht in:	The pharmacogenomics journal 2016-08, Vol.16 (4), p.375-387
Hauptverfasser:	Shirasaka, Y, Chaudhry, A S, McDonald, M, Prasad, B, Wong, T, Calamia, J C, Fohner, A, Thornton, T A, Isoherranen, N, Unadkat, J D, Rettie, A E, Schuetz, E G, Thummel, K E
Format:	Artikel
Sprache:	eng
Schlagworte:	38/23 38/77 631/208/205 82/58 82/80 Activation, Metabolic Adolescent Adult Aged Aged, 80 and over Biomedical and Life Sciences Biomedicine Child Child, Preschool Clopidogrel Cytochrome P-450 Cytochrome P-450 CYP2C19 - genetics Cytochrome P-450 CYP2C19 - metabolism Cytochrome P-450 Enzyme System - metabolism Drug metabolism Female Gene Expression Gene Expression Regulation, Enzymologic Gene Frequency Genetic aspects Genetic variation Genotype Health aspects Human Genetics Humans Hydroxylation Infant Infant, Newborn Kinetics Linear Models Liver - enzymology Male Mephenytoin - metabolism Microsomes, Liver - enzymology Middle Aged Multivariate Analysis Oncology Original original-article Oxidation-Reduction Oxidoreductases Pharmacogenomic Variants - genetics Pharmacotherapy Phenotype Properties Psychopharmacology Substrate Specificity Ticlopidine - analogs & derivatives Ticlopidine - metabolism Young Adult
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Zusammenfassung:	Large interindividual variability has been observed in the metabolism of CYP2C19 substrates in vivo . The study aimed to evaluate sources of this variability in CYP2C19 activity, focusing on CYP2C19 diplotypes and the cytochrome P 450 oxidoreductase (POR). CYP2C19 gene analysis was carried out on 347 human liver samples. CYP2C19 activity assayed using human liver microsomes confirmed a significant a priori predicted rank order for (S)-mephenytoin hydroxylase activity of CYP2C1917/17 > 1B/17 > 1B/1B > 2A/17 > 1B/2A > 2A/2A diplotypes. In a multivariate analysis, the CYP2C192A allele and POR protein content were associated with CYP2C19 activity. Further analysis indicated a strong effect of the CYP2C192A , but not the *17 , allele on both metabolic steps in the conversion of clopidogrel to its active metabolite. The present study demonstrates that interindividual variability in CYP2C19 activity is due to differences in both CYP2C19 protein content associated with gene diplotypes and the POR concentration.
ISSN:	1470-269X 1473-1150
DOI:	10.1038/tpj.2015.58