Biochemical and Biophysical Research Communications
Naphthalene toxicity in mice and aryl hydrocarbon receptor-mediated CYPs
Section snippets
Methods
Chemicals. Naphthalene and dimethyl sulfoxide were obtained from Fisher Scientific; 5-phenyl-1-pentyne was purchased from GFS (Columbus OH); TCDD was purchased from Accustandard, Inc. (New Haven, CT).
Mice. Ahr−/−, Cyp1a1−/−, and Cyp1a2−/− knockout mice were generated from in-house breeding colonies, and wild-type littermates were used as controls. Generation of the respective knockout mouse lines has been previously described [25], [26], [27], and these mice are maintained on the C57BL/6J
Knockout mouse studies
Wild-type, Cyp1a1−/−, and Cyp1a2−/− mice treated with 5-phenyl-1-pentyne + NP showed no overt sign of toxicity 18 h after treatment and were completely protected from the olfactory toxicity of NP. In contrast, the non-pretreated NP-treated wild-type, Cyp1a1−/−, and Cyp1a2−/− mice showed labored breathing and hemorrhagic lungs upon sacrifice, as well as nearly 100% sloughing of the olfactory mucosa (Fig. 1). Ahr−/− mice were similarly not protected from NP-induced olfactory mucosal degeneration and
Discussion
The results of our in vivo NP treatment studies revealed that mice in which the Ahr gene is ablated are not protected from NP cytotoxicity. We also investigated the impact of the absence of the Cyp1a1 and Cyp1a2 genes on susceptibility to NP-induced respiratory tract damage, given that both genes are inducible in lung, and the expressed proteins have been shown to convert NP to NP-1,2-oxide in vitro[15], [16], [31]. NP did not stimulate gene transcription via the AHR in our study, suggesting
Acknowledgments
This work was supported by NIH Grants R01 ES08147 (D.W.N.) and P30 ES06096 (M.B.G., D.W.N., A.P., and T.P.D.).
References (34)
- et al.
Cytotoxicity and mutagenicity of polycyclic aromatic hydrocarbon ortho-quinones produced by dihydrodiol dehydrogenase
Chem. Biol. Interact.
(1996) - et al.
Biological oxidations and P450 reactions. Recombinant mouse CYP1B1 expressed in Escherichia coli exhibits selective binding by polycyclic hydrocarbons and metabolism which parallels C3H10T1/2 cell microsomes, but differs from human recombinant CYP1B1
Arch. Biochem. Biophys.
(1997) - et al.
Predictive value of comparative molecular field analysis modelling of naphthalene inhibition of human CYP2A6 and mouse CYP2A5 enzymes
Toxicol. In Vitro
(2003) - et al.
Differential stereoselectivity of cytochromes P-450b and P-450c in the formation of naphthalene and anthracene 1,2-oxides. The role of epoxide hydrolase in determining the enantiomer composition of the 1,2-dihydrodiols formed
J. Biol. Chem.
(1985) - et al.
Cloning and expression of CYP2F3, a cytochrome P450 that bioactivates the selective pneumotoxins 3-methylindole and naphthalene
Arch. Biochem. Biophys.
(1998) - et al.
Targeted knockout of Cyp1a1 gene does not alter hepatic constitutive expression of other genes in the mouse [Ah] battery
Biochem. Biophys. Res. Commun.
(2000) Histopathologic examination of the rat nasal cavity
Fundam. Appl. Toxicol.
(1981)- et al.
Tissue- and cell type-specific expression of cytochrome P450 1A1 and cytochrome P450 1A2 mRNA in the mouse localized in situ hybridization
Biochem. Pharmacol.
(1999) - et al.
Mechanism-based inactivation of cytochromes P450 2E1 and 2B1 by 5-phenyl-1-pentyne
Arch. Biochem. Biophys.
(1998) - et al.
The carcinogenic potential of the gas phase of environmental tobacco smoke
Carcinogenesis
(1997)