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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on August 11, 2005; DOI: 10.1124/jpet.105.091181

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Tracy C DeLozier
Sherry J Coulter
Joyce A Goldstein
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Received for publication June 20, 2005.
Revised August 5, 2005.
Accepted for publication August 8, 2005.

Functional characterization of novel allelic variants of CYP2C9 recently discovered in Southeast Asians

Tracy C DeLozier 1, Soo-Chin Lee 2, Sherry J Coulter 1, Boon Cher Goh 2, Joyce A Goldstein 1*

1 Human Metabolism Section, Laboratoary of Pharmacology and Chemistry, NIEHS 2 Department of Hematology-Oncology, National University Hospital, Singapore

* Address correspondence to: E-mail: goldste1{at}niehs.nih.gov

Abstract

CYP2C9 was recently resequenced in 150 Asian subjects from Singapore. Several new coding variants were reported, and these variants are now named CYP2C9*14 (R125H), CYP2C9*15 (S162X), CYP2C9*16 (T299A), CYP2C9*17 (P382S), CYP2C9*18 (D397A), and CYP2C9*19 (Q454H). The CYP2C9*18 variant also contained an I359L change previously associated with the CYP2C9*3 allele. In this study, we assessed the functional consequences of the new coding changes. cDNAs containing each of the new coding changes were constructed by site- directed mutagenesis and expressed in a bacterial cDNA expression system, the allelic proteins were partially purified, and their ability to hydroxylate a prototype CYP2C9 substrate was assayed. Expression of cDNAs in E. coli containing either the D397A change or the S162X (premature stop codon) could not be detected either spectrally or at the apoprotein level. CYP2C9.14 and CYP2C9.16 exhibited 80-90% lower catalytic activity toward tolbutamide at two substrate concentrations compared to wild-type CYP2C9.1. Kinetic analysis confirmed that CYP2C9.14 and CYP2C9.16 have a higher Km and a >90% lower intrinsic clearance of tolbutamide compared to wild type CYP2C9.1. Both CYP2C9.17 and CYP2C9.19 proteins exhibited modest 30%-40% decreases in catalytic activity towards tolbutamide. Thus, CYP2C9*15 and CYP2C9*18 may represent null alleles, while CYP2C9*14 and CYP2C9*16 allelic variants produce proteins which are clearly catalytically defective in vitro, indicating the existence of new defective putative alleles of CYP2C9 in Asians.


Key words: CYP2C9, SNP, Southeast Asian, null alleles, polymorphisms, tolbutamide


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