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5024016 
Journal Article 
Abstract 
Role of AHR and CYP1A1 in naphthalene bioactivation 
Genter, M; Marlowe, J; Dragin, N; Kerzee, JK; Puga, A; Nebert, DW; Dalton, TP 
2006 
1 
Toxicological Sciences
ISSN: 1096-6080
EISSN: 1096-0929 
90 
1-S 
384 
English 
Naphthalene (NP) is a pesticide, combustion by-product, and component of jet fuel. NP has been designated a ?reasonably anticipated human carcinogen? because of positive responses in chronic carcinogenicity bioassays in both mice and rats, causing pulmonary adenomas in female mice and both nasal respiratory and olfactory tumors in rats. While CYP2F enzymes are widely regarded as responsible for NP bioactivation, other metabolic enzymes have been shown to metabolize NP to the 1,2-oxide metabolite in vitro, including CYP1A1 and CYP1A2. To investigate the role of these aryl hydrocarbon receptor (AHR)-mediated enzymes in NP toxicity, we took two approaches. First, NP was assessed for its ability to activate transcription via the AHR in an in vitro luciferase reporter assay and found to have no activity, whereas the known AHR ligand TCDD showed high activity. Second, in vivo studies involved dosing mice deficient in either the AHR or CYP1A1 with NP alone, or following pretreatment with the CYP2F2 inhibitor 5-phenyl-1-pentyne. Neither Ahr(-/-) nor Cyp1a1(-/-) knockout mice were protected from the olfactory mucosal or pulmonary toxicity of NP. On the other hand, CYP1A1-null mice treated with 5-phenyl-1-pentyne exhibited no evidence of pulmonary toxicity, and the olfactory mucosa in mice treated with the inhibitor plus NP showed no histological lesions. These results strongly suggest that enzymes controlled by the AHR do not contribute significantly to NP bioactivation in the intact animal, and provide further support that CYP2F enzymes are the major contributors to NP bioactivation.