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Molecular Pharmacology

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Research ArticleArticle

Identification and Functional Characterization of a New CYP2C9 Variant (CYP2C9*5) Expressed among African Americans

Leslie J. Dickmann, Allan E. Rettie, M. Byron Kneller, Richard B. Kim, Alastair J. J. Wood, C. Michael Stein, Grant R. Wilkinson and Ute I. Schwarz
Molecular Pharmacology August 2001, 60 (2) 382-387; DOI: https://doi.org/10.1124/mol.60.2.382
Leslie J. Dickmann
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Allan E. Rettie
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M. Byron Kneller
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Richard B. Kim
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Alastair J. J. Wood
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C. Michael Stein
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Grant R. Wilkinson
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Ute I. Schwarz
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Abstract

CYP2C9 is a polymorphic gene for which there are four known allelic variants; CYP2C9*1,CYP2C9*2, CYP2C9*3, andCYP2C9*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. TheCYP2C9*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 mvalue 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 ω-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 ofV 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.

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Molecular Pharmacology: 60 (2)
Molecular Pharmacology
Vol. 60, Issue 2
1 Aug 2001
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Research ArticleArticle

Identification and Functional Characterization of a New CYP2C9 Variant (CYP2C9*5) Expressed among African Americans

Leslie J. Dickmann, Allan E. Rettie, M. Byron Kneller, Richard B. Kim, Alastair J. J. Wood, C. Michael Stein, Grant R. Wilkinson and Ute I. Schwarz
Molecular Pharmacology August 1, 2001, 60 (2) 382-387; DOI: https://doi.org/10.1124/mol.60.2.382

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Research ArticleArticle

Identification and Functional Characterization of a New CYP2C9 Variant (CYP2C9*5) Expressed among African Americans

Leslie J. Dickmann, Allan E. Rettie, M. Byron Kneller, Richard B. Kim, Alastair J. J. Wood, C. Michael Stein, Grant R. Wilkinson and Ute I. Schwarz
Molecular Pharmacology August 1, 2001, 60 (2) 382-387; DOI: https://doi.org/10.1124/mol.60.2.382
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