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, Xinxin Ding

Research output: Contribution to journalArticle

29 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1144-1150
Number of pages7
JournalDrug Metabolism and Disposition
Volume40
Issue number6
DOIs
StatePublished - Jun 1 2012
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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    Wei, Y., Wu, H., Li, L., Liu, Z., Zhou, X., Zhang, Q. Y., Weng, Y., D'Agostino, J., Ling, G., Zhang, X., Kluetzman, K., Yao, Y., & Ding, X. (2012). Generation and characterization of a CYP2A13/2B6/2F1-transgenic mouse model. Drug Metabolism and Disposition, 40(6), 1144-1150. https://doi.org/10.1124/dmd.112.044826