Naphthalene toxicity in mice and aryl hydrocarbon receptor-mediated CYPs.
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.
Genter
Mary Beth
MB
Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati, Cincinnati, OH 45267-0056, USA. marybeth.genter@uc.edu
Marlowe
Jennifer
J
Kevin Kerzee
J
J
Dragin
Nadine
N
Puga
Alvaro
A
Dalton
Timothy P
TP
Nebert
Daniel W
DW
D000480:Alkynes / Q000494:pharmacology; D000818:Animals; D001555:Benzene Derivatives / Q000494:pharmacology; D019363:Cytochrome P-450 CYP1A1 / Q000187:drug effects / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000187:drug effects / Q000378:metabolism*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009281:Naphthalenes / Q000378:metabolism / Q000633:toxicity*; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014420:Turbinates / Q000187:drug effects / Q000473:pathology
D000480:Alkynes; D001555:Benzene Derivatives; D065607:Cytochrome P-450 Enzyme Inhibitors; D009281:Naphthalenes; D018336:Receptors, Aryl Hydrocarbon; C112922:5-phenyl-1-pentyne; D003577:Cytochrome P-450 Enzyme System; C110333:Cyp2f2 protein, mouse; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2