Abstract
The tissue- and species-selective toxicity of a number of pulmonary toxicants has been attributed to the presence and distribution of activating enzymes with high k cat in target airways of susceptible species. The mouse is especially sensitive to a variety of metabolically activated lung toxicants. Recombinant CYP2F2 (mouse) was recently shown to effectively metabolize the species-selective pulmonary toxicant naphthalene. Here we show that the pulmonary toxicants 1-nitronaphthalene and 2-methylnaphthalene are metabolized readily with high k cat values (17.1 and 67.6 min−1, respectively) to potentially cytotoxic intermediates at biologically relevantK m values (21.5 and 3.7 μM, respectively). Additionally, anthracene and benzo[a]pyrene are both metabolized by CYP2F2 (0.14 ± 0.04 and 0.04 ± 0.00 nmol/nmol/min, respectively), albeit at much lower rates. The levels of total CYP in mouse airways are considerably higher than those in parenchyma and trachea, and this is consistent with much higher rates of naphthalene metabolism in microsomal preparations from airways compared with the other subcompartments. The data suggest that CYP2F2 is a prominent cytochrome P450 in mouse lung that metabolizes a number of pulmonary toxicants. The presence of CYP2F2 may be important in the susceptibility of the mouse to metabolically activated pulmonary toxicants.
Footnotes
- Received August 16, 2000.
- Accepted October 20, 2000.
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Send reprint requests to: Dr. Alan Buckpitt, Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616. E-mail:arbuckpitt{at}ucdavis.edu
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↵1 Present address: Molecular Dynamics, 928 East Arques Ave., Sunnyvale, CA 94086.
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Supported by National Institute on Environmental Health Sciences 08408 and ES 04699. University of California-Davis is a National Institute on Environmental Health Sciences Center (ES 05707) and support for core facilities used in this work is gratefully acknowledged. M.A.S. was supported by T32 ES07059.
- The American Society for Pharmacology and Experimental Therapeutics
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