Identification and functional characterization of a new CYP2C9 variant (CYP2C9*5) expressed among African Americans.
Article Details
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Dickmann LJ, Rettie AE, Kneller MB, Kim RB, Wood AJ, Stein CM, Wilkinson GR, Schwarz UI
Identification and functional characterization of a new CYP2C9 variant (CYP2C9*5) expressed among African Americans.
Mol Pharmacol. 2001 Aug;60(2):382-7.
- PubMed ID
- 11455026 [ View in PubMed]
- Abstract
CYP2C9 is a polymorphic gene for which there are four known allelic variants; CYP2C9*1, CYP2C9*2, CYP2C9*3, and CYP2C9*4. In the present study, DNA from 140 European Americans and 120 African Americans was examined by single-strand conformational polymorphism and restriction fragment length polymorphism analyses, resulting in the identification of a new CYP2C9 variant, CYP2C9*5. This variant is derived from a C1080G transversion in exon 7 of CYP2C9 that leads to an Asp360Glu substitution in the encoded protein. The CYP2C9*5 variant was found to be expressed only in African Americans, such that approximately 3% of this population carries the CYP2C9*5 allele. The variant was expressed in, and purified from, insect cells infected with a recombinant baculovirus. Comparative kinetic studies using the purified wild-type protein CYP2C9*1; the Ile359Leu variant, CYP2C9*3; and the Asp360Glu variant, CYP2C9*5 were carried out using (S)-warfarin, diclofenac, and lauric acid as substrates. The major effect of the Asp360Glu mutation was to increase the K(m) value relative to that of CYP2C9*1 for all three substrates: 12-fold higher for (S)-warfarin 7-hydroxylation, 5-fold higher for the 4'-hydroxylation of diclofenac, and 3-fold higher for the omega-1 hydroxylation of lauric acid. V(max) values differed less than K(m) values between the CYP2C9*1 and CYP2C9*5 proteins. In vitro intrinsic clearances for CYP2C9*5, calculated as the ratio of V(max)/K(m), ranged from 8 to 18% of CYP2C9*1 values. The corresponding ratio for CYP2C9*3 was 4 to 13%. Accordingly, the in vitro data suggest that carriers of the CYP2C9*5 allele would eliminate CYP2C9 substrates at slower rates relative to persons expressing the wild-type protein.
DrugBank Data that Cites this Article
- Polypeptides
Name UniProt ID Cytochrome P450 2C9 P11712 Details - Pharmaco-genomics
Drug Interacting Gene/Enzyme Allele name Genotypes Defining change(s) Type(s) Description Details Phenytoin Cytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712CYP2C9*5 Not Available - 1080C>G (rs28371686)
Effect Inferred Poor drug metabolizer, lower dose requirements Details Celecoxib Cytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712CYP2C9*5 Not Available - 1080C>G (rs28371686)
Effect Inferred Poor drug metabolizer, lower dose requirements Details Warfarin Cytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712CYP2C9*5 Not Available - 1080C>G (rs28371686)
Effect Inferred Poor drug metabolizer, lower dose requirements Details Clopidogrel Cytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712CYP2C9*5 Not Available - 1080C>G (rs28371686)
Effect Inferred Poor drug metabolizer, lower dose requirements, higher risk for drug-drug interactions Details Acetylsalicylic acid Cytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712CYP2C9*5 Not Available - 1080C>G (rs28371686)
Effect Inferred Poor drug metabolizer, lower dose requirements Details Glipizide Cytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712CYP2C9*5 Not Available - 1080C>G (rs28371686)
Effect Inferred Poor drug metabolizer, lower dose requirements Details Tolbutamide Cytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712CYP2C9*5 Not Available - 1080C>G (rs28371686)
Effect Inferred Poor drug metabolizer, lower dose requirements Details Acenocoumarol Cytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712CYP2C9*5 Not Available - 1080C>G (rs28371686)
Effect Inferred Poor drug metabolizer, associated with lower dose requirement. Details Phenprocoumon Cytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712CYP2C9*5 Not Available - 1080C>G (rs28371686)
ADR Inferred Associated with delayed stabilization. If carrier of rs9934438 as well, increased risk of severe overanticoagulation. Details