Title: Naphthalene toxicity in mice and aryl hydrocarbon receptor-mediated CYPs.

Authors: Genter, Mary Beth; Marlowe, Jennifer; Kevin Kerzee, J; Dragin, Nadine; Puga, Alvaro; Dalton, Timothy P; Nebert, Daniel W

Published In Biochem Biophys Res Commun, (2006 Sep 15)

Abstract: Naphthalene (NP) has been designated a "reasonably anticipated human carcinogen" because of positive responses in carcinogenicity bioassays in rodents. Whereas CYP2F enzymes are widely regarded as responsible for NP bioactivation, other metabolic enzymes--including CYP1A1 and CYP1A2--produce NP-1,2-oxide in vitro. We investigated the role of these aryl hydrocarbon receptor (AHR)-mediated enzymes in NP toxicity in two ways. First, NP was assessed for the ability to activate transcription via the AHR in an in vitro luciferase reporter assay and was found to have no activity. Second, mice deficient in AHR, CYP1A1 or CYP1A2 were dosed with NP alone, or following pretreatment with the CYP2F inhibitor 5-phenyl-1-pentyne. None of the knockout mice were protected from olfactory toxicity of NP. In contrast, CYP1A1- and CYP1A2-null mice pretreated with 5-phenyl-1-pentyne exhibited no NP olfactory toxicity. These results suggest that AHR-mediated enzymes do not contribute significantly to NP bioactivation in the intact animal.

PubMed ID: 16876762

MeSH Terms: Alkynes/pharmacology; Animals; Benzene Derivatives/pharmacology; Cytochrome P-450 CYP1A1/drug effects; Cytochrome P-450 CYP1A1/metabolism*; Cytochrome P-450 CYP1A2/drug effects; Cytochrome P-450 CYP1A2/metabolism*; Cytochrome P-450 Enzyme System/antagonists & inhibitors; Cytochrome P-450 Enzyme System/metabolism*; Gene Expression Regulation/drug effects; Humans; Mice; Mice, Knockout; Naphthalenes/metabolism; Naphthalenes/toxicity*; Receptors, Aryl Hydrocarbon/drug effects; Receptors, Aryl Hydrocarbon/metabolism*; Signal Transduction/drug effects; Turbinates/drug effects; Turbinates/pathology