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 P450 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 CYP2C19*17/*17 > *1B/*17 > *1B/*1B > *2A/*17 > *1B/*2A > *2A/*2A diplotypes. In a multivariate analysis, the CYP2C19*2A allele and POR protein content were associated with CYP2C19 activity. Further analysis indicated a strong effect of the CYP2C19*2A, 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.The Pharmacogenomics Journal advance online publication, 1 September 2015; doi:10.1038/tpj.2015.58.
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, USA.
Y
Y
Shirasaka
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
A S
AS
Chaudhry
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, WA, USA.
M
M
McDonald
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, USA.
B
B
Prasad
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, USA.
T
T
Wong
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, USA.
J C
JC
Calamia
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, USA.
A
A
Fohner
Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA, USA.
T A
TA
Thornton
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, USA.
N
N
Isoherranen
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, USA.
J D
JD
Unadkat
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, WA, USA.
A E
AE
Rettie
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
E G
EG
Schuetz
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, USA.
K E
KE
Thummel
D065767:Activation, Metabolic; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics* / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D006900:Hydroxylation; D007223:Infant; D007231:Infant, Newborn; D007700:Kinetics; D016014:Linear Models; D008099:Liver / Q000201:enzymology*; D008297:Male; D008617:Mephenytoin / Q000378:metabolism*; D008862:Microsomes, Liver / Q000201:enzymology; D008875:Middle Aged; D015999:Multivariate Analysis; D010084:Oxidation-Reduction; D000071184:Pharmacogenomic Variants / Q000235:genetics*; D010641:Phenotype; D013379:Substrate Specificity; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000378:metabolism; D055815:Young Adult
C000602470:POR protein, human; D003577:Cytochrome P-450 Enzyme System; D000077144:Clopidogrel; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine; D008617:Mephenytoin