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-l-pentyne. None of the knockout mice were protected from olfactory toxicity of NP. In contrast, CYP1A1- and CYP1A2-null mice pretreated with 5-phenyl-l-pentyne exhibited no NP olfactory toxicity. These results suggest that AHR-mediated enzymes do not contribute significantly to NP bioactivation in the intact animal. (c) 2006 Elsevier Inc. All rights reserved.