The CYP2F enzymes, abundantly expressed in the respiratory tract, are active toward many xenobiotic compounds, including naphthalene (NA). However, the precise roles of these enzymes in tissue-selective chemical toxicity have been difficult to resolve. A Cyp2f2-null mouse was generated in this study, by disrupting the Cyp2f2 4th exon. Homozygous Cyp2f2-null mice, which had no CYP2F2 expression, and did not show any changes in the expression of other Cyp genes examined, were viable and fertile, and without any in utero lethality or developmental deficits. The loss of CYP2F2 expression led to substantial decreases in the in vitro catalytic efficiency of microsomal NA epoxygenases in lung (up to ~160 fold), liver (~3 fold), and nasal olfactory mucosa (OM, up to ~16 fold), and significant decreases in rates of systemic NA (300 mg/kg, i.p.) clearance. The Cyp2f2-null mice were largely resistant to NA-induced cytotoxicity, when examined at 24 h after NA dosing (at 300 mg/kg, i.p.), and to NA-induced depletion of total nonprotein sulfhydryl (NPSH), examined at 2 h after dosing, in the lungs. In contrast, the loss of CYP2F2 expression did not alleviate NA-induced NPSH depletion or tissue toxicity in the OM. Clearly, mouse CYP2F2 plays an essential role in the bioactivation and toxicity of NA in the lung, but not in the OM. The Cyp2f2-null mouse should be valuable for studies on the role of CYP2F2 in the metabolism and toxicity of numerous other xenobiotic compounds, and for future production of a CYP2F1-humanized mouse.
- Received May 31, 2011.
- Revision received June 22, 2011.
- Accepted June 23, 2011.
- The American Society for Pharmacology and Experimental Therapeutics