Metabolic capabilities of CYP2F2 with various pulmonary toxicants and its relative abundance in mouse lung subcompartments.
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 relevant K(m) values (21.5 and 3.7 microM, 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.
Shultz
M A
MA
Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis 95616, USA.
Morin
D
D
Chang
A M
AM
Buckpitt
A
A
D000818:Animals; D000873:Anthracenes / Q000378:metabolism; D001564:Benzo(a)pyrene / Q000378:metabolism; D001711:Biotransformation / Q000187:drug effects; D002384:Catalysis; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D007202:Indicators and Reagents; D008168:Lung / Q000201:enzymology*; D008171:Lung Diseases / Q000139:chemically induced* / Q000201:enzymology*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D009281:Naphthalenes / Q000378:metabolism / Q000633:toxicity; D014132:Trachea / Q000201:enzymology / Q000378:metabolism
D000873:Anthracenes; D007202:Indicators and Reagents; D009281:Naphthalenes; D001564:Benzo(a)pyrene; D003577:Cytochrome P-450 Enzyme System; C016614:1-nitronaphthalene; C110333:Cyp2f2 protein, mouse; C027384:2-methylnaphthalene