QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.104.075440v1 312/2/857    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Baldwin, R. M. Articles by Buckpitt, A. R. Search for Related Content PubMed PubMed Citation Articles by Baldwin, R. M. Articles by Buckpitt, A. R. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Nucleotide Protein UniGene Compound via MeSH Substance via MeSH Hazardous Substances DB 1-NITRONAPHTHALENE NAPHTHALENE Medline Plus Health Information Lung Diseases

TOXICOLOGY

Bioactivation of the Pulmonary Toxicants Naphthalene and 1-Nitronaphthalene by Rat CYP2F4

Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California

Naphthalene, a ubiquitous environmental contaminant, produces cytotoxicity in nonciliated bronchiolar epithelial (Clara) cells in mice; rats are refractory to lung cytotoxicity from naphthalene. In contrast, 1-nitronaphthalene is a potent toxicant in both species. Naphthalene is metabolized by CYP2F to a 1,2-epoxide, the first and obligate step in events leading to cytotoxicity. 1-Nitronaphthalene is metabolized to both the 5,6- and the 7,8-epoxides with the 7,8-epoxide predominating in lung. Previous studies have demonstrated recombinant CYP2F2 (mouse) to efficiently metabolize both naphthalene and 1-nitronaphthalene. To better understand the mechanism for the unique toxicity profiles for both compounds, a CYP2F ortholog (CYP2F4) was isolated from rat lung and expressed using a baculovirus system. Recombinant CYP2F4 efficiently generates 1R,2S-naphthalene oxide (K_m = 3 µM, V_max = 107 min^-1) and the 5,6- and 7,8-epoxides of 1-nitronaphthalene (K_m = 18 µM, V_max = 25 min^-1 based on total generated glutathione conjugates). Kinetics and regio/stereoselectivity of rat CYP2F4 were indistinguishable from mouse CYP2F2. These results, combined with our recent immunomapping studies demonstrating minimal pulmonary CYP2F expression in rats, indicate that CYP2F expression is the factor most clearly associated with susceptibility to naphthalene-induced pneumotoxicity. CYP2F4 failed to display an enhanced ability to bioactivate 1-nitronaphthalene, an ability that could have potentially compensated for the lower CYP2F pulmonary expression levels in the rat, yet equal species susceptibilities. These results suggest the importance of other P450 enzymes in the epoxidation/bioactivation of 1-nitronaphthalene. Expression of recombinant CYP2F1 (human) yielded an immunoreactive protein with no detectable CO-difference spectrum suggesting inadequate heme incorporation.

Address correspondence to: R. Michael Baldwin, Veterinary Medicine: Molecular Biosciences, 1311 Haring Hall, UC Davis, Davis, CA 95616. E:mail: rmbaldwin{at}ucdavis-alumni.com

This article has been cited by other articles:

				K. C. Day, C. G. Plopper, and M. V. Fanucchi Age-specific pulmonary cytochrome P-450 3A1 expression in postnatal and adult rats Am J Physiol Lung Cell Mol Physiol, July 1, 2006; 291(1): L75 - L83. [Abstract] [Full Text] [PDF]

				P.-G. Forkert, R. M. Baldwin, B. Millen, L. H. Lash, D. A. Putt, M. A. Shultz, and K. S. Collins PULMONARY BIOACTIVATION OF TRICHLOROETHYLENE TO CHLORAL HYDRATE: RELATIVE CONTRIBUTIONS OF CYP2E1, CYP2F, AND CYP2B1 Drug Metab. Dispos., October 1, 2005; 33(10): 1429 - 1437. [Abstract] [Full Text] [PDF]