JPET Introducing ALZET?ew Model 2006 Pump

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zhang, X.
Right arrow Articles by Ding, X.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zhang, X.
Right arrow Articles by Ding, X.

Vol. 302, Issue 2, 416-423, August 2002

Genetic Polymorphisms of the Human CYP2A13 Gene: Identification of Single-Nucleotide Polymorphisms and Functional Characterization of an Arg257Cys Variant

Xiuling Zhang, Ting Su, Qing-Yu Zhang, Jun Gu, Michele Caggana, Hongming Li and Xinxin Ding

Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, Albany, New York

Human cytochrome P450 2A13 (CYP2A13), which is highly efficient in the metabolic activation of a major tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), may play important roles in xenobiotic toxicity and tobacco-related tumorigenesis in the respiratory tract. The aim of this study was to identify any genetic polymorphisms of the CYP2A13 gene, which may alter the metabolic capacities of the enzyme. Polymerase chain reaction (PCR) single-strand conformational polymorphism analysis was used to identify single-nucleotide polymorphisms (SNPs) in all of the exons and at the exon-intron boundaries, and PCR-restriction fragment length polymorphism analysis and DNA sequencing were used to determine the frequencies of the newly identified variant alleles in the four major ethnic groups. Blood spot DNA from more than 100 individuals was used for these analyses. Seven variant alleles were found, but only one SNP was detected in the coding region, in exon 5, leading to an Arg257Cys amino acid change. The frequencies of the Arg257Cys allele in white, black, Hispanic, and Asian individuals are 1.9%, 14.4%, 5.8%, and 7.7%, respectively. Functional analysis of the variant protein was performed following its heterologous expression. The Arg257Cys variant was 37 to 56% less active than the wild-type Arg-257 protein toward all substrates tested. With NNK, Cys-257 had higher Km and lower Vmax values than did Arg-257, with a >2-fold decrease in catalytic efficiency. The Arg257Cys mutation could provide some protection against xenobiotic toxicity in the respiratory tract to individuals who are homozygous for the Cys-257 allele.

0022-3565/02/3022-0416$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 J. Pharmacol. Exp. Ther.Home page
X. Zhang, J. D'Agostino, H. Wu, Q.-Y. Zhang, L. von Weymarn, S. E. Murphy, and X. Ding
CYP2A13: Variable Expression and Role in Human Lung Microsomal Metabolic Activation of the Tobacco-Specific Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone
J. Pharmacol. Exp. Ther., November 1, 2007; 323(2): 570 - 578.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
P. J. Brown, L. L. Bedard, K. R. Reid, D. Petsikas, and T. E. Massey
Analysis of CYP2A Contributions to Metabolism of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone in Human Peripheral Lung Microsomes
Drug Metab. Dispos., November 1, 2007; 35(11): 2086 - 2094.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
B. D. Smith, J. L. Sanders, P. R. Porubsky, G. H. Lushington, C. D. Stout, and E. E. Scott
Structure of the Human Lung Cytochrome P450 2A13
J. Biol. Chem., June 8, 2007; 282(23): 17306 - 17313.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
S.-L. Wang, X.-Y. He, J. Shen, J.-S. Wang, and J.-Y. Hong
The Missense Genetic Polymorphisms of Human CYP2A13: Functional Significance in Carcinogen Activation and Identification of A Null Allelic Variant
Toxicol. Sci., November 1, 2006; 94(1): 38 - 45.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
L. B. von Weymarn, Q.-Y. Zhang, X. Ding, and P. F. Hollenberg
Effects of 8-methoxypsoralen on cytochrome P450 2A13
Carcinogenesis, March 1, 2005; 26(3): 621 - 629.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
X.-Y. He, J. Shen, X. Ding, A. Y. H. Lu, and J.-Y. Hong
IDENTIFICATION OF CRITICAL AMINO ACID RESIDUES OF HUMAN CYP2A13 FOR THE METABOLIC ACTIVATION OF 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE, A TOBACCO-SPECIFIC CARCINOGEN
Drug Metab. Dispos., December 1, 2004; 32(12): 1516 - 1521.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
X. Zhang, M. Caggana, T. L. Cutler, and X. Ding
Development of a Real-Time Polymerase Chain Reaction-Based Method for the Measurement of Relative Allelic Expression and Identification of CYP2A13 Alleles with Decreased Expression in Human Lung
J. Pharmacol. Exp. Ther., October 1, 2004; 311(1): 373 - 381.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
H. Wang, W. Tan, B. Hao, X. Miao, G. Zhou, F. He, and D. Lin
Substantial Reduction in Risk of Lung Adenocarcinoma Associated with Genetic Polymorphism in CYP2A13, the Most Active Cytochrome P450 for the Metabolic Activation of Tobacco-Specific Carcinogen NNK
Cancer Res., November 15, 2003; 63(22): 8057 - 8061.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
J. R. Jalas, X. Ding, and S. E. Murphy
COMPARATIVE METABOLISM OF THE TOBACCO-SPECIFIC NITROSAMINES 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE AND 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANOL BY RAT CYTOCHROME P450 2A3 AND HUMAN CYTOCHROME P450 2A13
Drug Metab. Dispos., October 1, 2003; 31(10): 1199 - 1202.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
X. Zhang, Y. Chen, Y. Liu, X. Ren, Q.-Y. Zhang, M. Caggana, and X. Ding
SINGLE NUCLEOTIDE POLYMORPHISMS OF THE HUMAN CYP2A13 GENE: EVIDENCE FOR A NULL ALLELE
Drug Metab. Dispos., September 1, 2003; 31(9): 1081 - 1085.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
G. B. J. Smith, J. R. Bend, L. L. Bedard, K. R. Reid, D. Petsikas, and T. E. Massey
BIOTRANSFORMATION OF 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE (NNK) IN PERIPHERAL HUMAN LUNG MICROSOMES
Drug Metab. Dispos., September 1, 2003; 31(9): 1134 - 1141.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2002 by the American Society for Pharmacology and Experimental Therapeutics.