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ToxSci Advance Access published online on August 17, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl081
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received May 18, 2006
Accepted July 24, 2006

Carcinogenicity

The Missense Genetic Polymorphisms of Human CYP2A13: Functional Significance in Carcinogen Activation and Identification of A Null Allelic Variant

Shou-Lin Wang 1, Xiao-Yang He 2, Jian Shen 3, Jia-Sheng Wang 4, and Jun-Yan Hong 2 *

1 School of Public Health/Environmental and Occupational Health Sciences Institute, University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854, USA; Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China
2 School of Public Health/Environmental and Occupational Health Sciences Institute, University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854, USA
3 Sanofi-Aventis Pharmaceutical Inc., Bridgewater, NJ 08807, USA
4 Department of Environmental Toxicology/The Institute of Environmental and Human Health, Texas Tech University, Lubbock, TX 79409, USA

* To whom correspondence should be addressed.
Jun-Yan Hong, E-mail: jyhong{at}eohsi.rutgers.edu


  Abstract

Cytochrome P450 2A13 (CYP2A13), an enzyme predominantly expressed in human respiratory tissues, is highly efficient for the metabolic activation of two suspected human lung carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and aflatoxin B1 (AFB1). Functional genetic polymorphisms of CYP2A13 may therefore be an important factor in human susceptibility to related lung cancers. Among the reported CYP2A13 polymorphisms with missense variations, only CYP2A13*2 variant (containing either a single or double variation of R25Q and R257C) was studied for its NNK-metabolizing activity. The present study demonstrated that there was no remarkable difference in AFB1- and NNK-induced toxicity between the Flp-In CHO cells stably expressing wild-type CYP2A13 and the cells expressing the individual polymorphic variants R25Q, D158E, R257C, R25Q/R257C, V323L, F453Y and R494C. In contrast, cells transfected with R101Q variant cDNA, same as the vector control cells, showed no significant death even at highest concentrations of AFB1 (10 µM) and NNK (200 µM). This result correlated with the lack of CYP2A13 protein in the R101Q-CHO cells, although the genomic integration of transfected R101Q cDNA and the expression of R101Q mRNA were clearly demonstrated in these stable transfectants. Consistent with the possibility that the variation might reduce the protein stability, R101Q variant protein expressed in insect cells showed a loss of P450 peak and coumarin 7-hydroxylase activity as well as an increased susceptibility to limited protein digestion. Thus, the R101Q polymorphic change results in a null allelic variant of CYP2A13. Our results should be useful in designing and interpreting molecular epidemiological studies related to CYP2A13 genetic polymorphisms.

Keywords: cytochrome P450 2A13; genetic polymorphism; metabolic activation; aflatoxin B1; 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.
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