Discovery of new potentially defective alleles of human CYP2C9.

Article Details

Citation

Blaisdell J, Jorge-Nebert LF, Coulter S, Ferguson SS, Lee SJ, Chanas B, Xi T, Mohrenweiser H, Ghanayem B, Goldstein JA

Discovery of new potentially defective alleles of human CYP2C9.

Pharmacogenetics. 2004 Aug;14(8):527-37.

PubMed ID
15284535 [ View in PubMed
]
Abstract

CYP2C9 is a clinically important enzyme, responsible for the metabolism of numerous clinically important therapeutic drugs. In the present study, we discovered 38 single nucleotide polymorphisms in CYP2C9 by resequencing of genomic DNA from 92 individuals from three different racial groups. Haplotype analysis predicted that there are at least 21 alleles of CYP2C9 in this group of individuals. Six new alleles were identified that contained coding changes: L19I (CYP2C9*7), R150H (CYP2C9*8), H251R (CYP2C9*9), E272G (CYP2C9*10), R335W(CYP2C9*11) and P489S (CYP2C9*12). When expressed in a bacterial cDNA expression system, several alleles exhibited altered catalytic activity. CYP2C9*11 appeared to be a putative poor metabolizer allele, exhibiting a three-fold increase in the Km and more than a two-fold decrease in the intrinsic clearance for tolbutamide. Examination of the crystal structure of human CYP2C9 reveals that R335 is located in the turn between the J and J' helices and forms a hydrogen-bonding ion pair with D341 from the J' helix. Abolishing this interaction in CYP2C9*11 individuals could destabilize the secondary structure and alter the substrate affinity. This new putative poor metabolizer (PM) allele was found in Africans. A second potentially PM allele CYP2C9*12 found in a racially unidentified sample also exhibited a modest decrease in the Vmax and the intrinsic clearance for tolbutamide in a recombinant system. Further clinical studies are needed to determine the effect of these new polymorphisms on the metabolism of CYP2C9 substrates.

DrugBank Data that Cites this Article

Pharmaco-genomics
DrugInteracting Gene/EnzymeAllele nameGenotypesDefining change(s)Type(s)DescriptionDetails
PhenytoinCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*8Not AvailableEffect InferredPoor drug metabolizer, lower dose requirementsDetails
PhenytoinCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*11Not AvailableEffect InferredPoor drug metabolizer, lower dose requirementsDetails
PhenytoinCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*12Not AvailableEffect InferredPoor drug metabolizer, lower dose requirementsDetails
CelecoxibCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*8Not AvailableEffect InferredPoor drug metabolizer, lower dose requirementsDetails
CelecoxibCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*11Not AvailableEffect InferredPoor drug metabolizer, lower dose requirementsDetails
CelecoxibCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*12Not AvailableEffect InferredPoor drug metabolizer, lower dose requirementsDetails
WarfarinCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*8Not AvailableEffect InferredPoor drug metabolizer, lower dose requirementsDetails
WarfarinCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*11Not AvailableEffect InferredPoor drug metabolizer, lower dose requirementsDetails
WarfarinCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*12Not AvailableEffect InferredPoor drug metabolizer, lower dose requirementsDetails
ClopidogrelCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*8Not AvailableEffect InferredPoor drug metabolizer, lower dose requirements, higher risk for drug-drug interactionsDetails
ClopidogrelCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*11Not AvailableEffect InferredPoor drug metabolizer, lower dose requirements, higher risk for drug-drug interactionsDetails
ClopidogrelCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*12Not AvailableEffect InferredPoor drug metabolizer, lower dose requirements, higher risk for drug-drug interactionsDetails
Acetylsalicylic acidCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*8Not AvailableEffect InferredPoor drug metabolizer, lower dose requirementsDetails
Acetylsalicylic acidCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*11Not AvailableEffect InferredPoor drug metabolizer, lower dose requirementsDetails
Acetylsalicylic acidCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*12Not AvailableEffect InferredPoor drug metabolizer, lower dose requirementsDetails
GlipizideCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*8Not AvailableEffect InferredPoor drug metabolizer, lower dose requirementsDetails
GlipizideCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*11Not AvailableEffect InferredPoor drug metabolizer, lower dose requirementsDetails
GlipizideCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*12Not AvailableEffect InferredPoor drug metabolizer, lower dose requirementsDetails
TolbutamideCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*8Not AvailableEffect InferredPoor drug metabolizer, lower dose requirementsDetails
TolbutamideCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*11Not AvailableEffect InferredPoor drug metabolizer, lower dose requirementsDetails
TolbutamideCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*12Not AvailableEffect InferredPoor drug metabolizer, lower dose requirementsDetails
AcenocoumarolCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*8Not AvailableEffect InferredPoor drug metabolizer, associated with lower dose requirement.Details
AcenocoumarolCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*11Not AvailableEffect InferredPoor drug metabolizer, associated with lower dose requirement.Details
AcenocoumarolCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*12Not AvailableEffect InferredPoor drug metabolizer, associated with lower dose requirement.Details
PhenprocoumonCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*8Not AvailableADR InferredAssociated with delayed stabilization. If carrier of rs9934438 as well, increased risk of severe overanticoagulation.Details
PhenprocoumonCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*11Not AvailableADR InferredAssociated with delayed stabilization. If carrier of rs9934438 as well, increased risk of severe overanticoagulation.Details
PhenprocoumonCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*12Not AvailableADR InferredAssociated with delayed stabilization. If carrier of rs9934438 as well, increased risk of severe overanticoagulation.Details