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Research ArticleArticle

Generation and Characterization of a CYP2A13/2B6/2F1-Transgenic Mouse Model

Yuan Wei, Hong Wu, Lei Li, Zhihua Liu, Xin Zhou, Qing-Yu Zhang, Yan Weng, Jaime D'Agostino, Guoyu Ling, Xiuling Zhang, Kerri Kluetzman, Yunyi Yao and Xinxin Ding
Drug Metabolism and Disposition June 2012, 40 (6) 1144-1150; DOI: https://doi.org/10.1124/dmd.112.044826
Yuan Wei
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Hong Wu
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Lei Li
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Zhihua Liu
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Xin Zhou
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Qing-Yu Zhang
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Yan Weng
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Jaime D'Agostino
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Guoyu Ling
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Xiuling Zhang
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Kerri Kluetzman
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Yunyi Yao
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Xinxin Ding
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Abstract

CYP2A13, CYP2B6, and CYP2F1, which are encoded by neighboring cytochrome P450 genes on human chromosome 19, are active in the metabolic activation of many drugs, respiratory toxicants, and chemical carcinogens. To facilitate studies on the regulation and function of these human genes, we have generated a CYP2A13/2B6/2F1-transgenic (TG) mouse model (all *1 alleles). Homozygous transgenic mice are normal with respect to gross morphological features, development, and fertility. The tissue distribution of transgenic mRNA expression agreed well with the known respiratory tract-selective expression of CYP2A13 and CYP2F1 and hepatic expression of CYP2B6 in humans. CYP2A13 protein was detected through immunoblot analyses in the nasal mucosa (NM) (∼100 pmol/mg of microsomal protein; similar to the level of mouse CYP2A5) and the lung (∼0.2 pmol/mg of microsomal protein) but not in the liver of the TG mice. CYP2F1 protein, which could not be separated from mouse CYP2F2 in immunoblot analyses, was readily detected in the NM and lung but not the liver of TG/Cyp2f2-null mice, at levels 10- and 40-fold, respectively, lower than that of mouse CYP2F2 in the TG mice. CYP2B6 protein was detected in the liver (∼0.2 pmol/mg of microsomal protein) but not the NM or lung (with a detection limit of 0.04 pmol/mg of microsomal protein) of the TG mice. At least one transgenic protein (CYP2A13) seems to be active, because the NM of the TG mice had greater in vitro and in vivo activities in bioactivation of a CYP2A13 substrate, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (a lung carcinogen), than did the NM of wild-type mice.

Footnotes

  • This work was supported in part by the National Institutes of Health National Cancer Institute [Grant CA092596]; the National Institutes of Health National Institute of Environmental Health Sciences [Grant ES007462] (to X.D.); the National Institutes of Health National Institute of General Medical Sciences [Grant GM074249] (to Q.Z.); and a grant from the Styrene Information and Research Center (to X.D.).

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    http://dx.doi.org/10.1124/dmd.112.044826.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    BAC
    bacterial artificial chromosome
    NNK
    4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
    HPB
    4-hydroxy-1-(3-pyridyl)-1-butanone
    OPB
    4-oxo-4-(3-pyridyl)butanal
    O6-mG
    O6-methylguanine
    NM
    nasal mucosa
    LCM
    laser-capture microdissection
    bp
    base pair
    kbp
    kilo-base pair
    WT
    wild-type
    TG
    CYP2A13/2B6/2F1-transgenic
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    PCR
    polymerase chain reaction.

  • Received January 27, 2012.
  • Accepted March 5, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (6)
Drug Metabolism and Disposition
Vol. 40, Issue 6
1 Jun 2012
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Research ArticleArticle

CYP2A13/2B6/2F1-TRANSGENIC MICE

Yuan Wei, Hong Wu, Lei Li, Zhihua Liu, Xin Zhou, Qing-Yu Zhang, Yan Weng, Jaime D'Agostino, Guoyu Ling, Xiuling Zhang, Kerri Kluetzman, Yunyi Yao and Xinxin Ding
Drug Metabolism and Disposition June 1, 2012, 40 (6) 1144-1150; DOI: https://doi.org/10.1124/dmd.112.044826

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Research ArticleArticle

CYP2A13/2B6/2F1-TRANSGENIC MICE

Yuan Wei, Hong Wu, Lei Li, Zhihua Liu, Xin Zhou, Qing-Yu Zhang, Yan Weng, Jaime D'Agostino, Guoyu Ling, Xiuling Zhang, Kerri Kluetzman, Yunyi Yao and Xinxin Ding
Drug Metabolism and Disposition June 1, 2012, 40 (6) 1144-1150; DOI: https://doi.org/10.1124/dmd.112.044826
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