Abstract
CYP2A13, CYP2B6, and CYP2F1, neighboring cytochrome P450 (P450) genes on human chromosome 19, are active in the metabolic activation of many drugs, respiratory toxicants, and chemical carcinogens. In efforts to facilitate studies on the regulation and function of these human genes, we have generated a CYP2A13/2B6/2F1-transgenic (TG) mouse (all *1 alleles). Homozygous TG mice are normal in gross morphology, 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 by immunoblot analysis in the nasal mucosa (NM; ~100 pmol/mg microsomal protein; similar to the level of mouse CYP2A5) and the lung (~0.2 pmol/mg microsomal protein), but not in the liver, of the TG mouse. CYP2F1 protein, which could not be separated from mouse CYP2F2 by immunoblot analysis, was readily detected in NM and lung, but not liver, of a TG/Cyp2f2-null mouse, 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 microsomal protein), but not in NM or lung (at a detection limit of 0.04 pmol/mg microsomal protein), of the TG mice. At least one of the transgene (CYP2A13) appears to be active, as NM of the TG mice had greater in vitro and in vivo activities toward bioactivation of a CYP2A13 substrate, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a lung carcinogen, than did the NM of wild-type mice.
- Received February 3, 2012.
- Accepted March 5, 2012.
- The American Society for Pharmacology and Experimental Therapeutics