title: Mechanisms of olfactory toxicity of the herbicide 2,6-dichlorobenzonitrile: essential roles of CYP2A5 and target-tissue metabolic activation.
abstract: The herbicide 2,6-dichlorobenzonitril (DCBN) is a potent and tissue-specific toxicant to the olfactory mucosa (OM). The toxicity of DCBN is mediated by cytochrome P450 (P450)-catalyzed bioactivation; however, it is not known whether target-tissue metabolic activation is essential for toxicity. CYP2A5, expressed abundantly in both liver and OM, was previously found to be one of the P450 enzymes active in DCBN bioactivation in vitro. The aims of this study were to determine the role of CYP2A5 in DCBN toxicity in vivo, by comparing the extents of DCBN toxicity between Cyp2a5-null and wild-type (WT) mice, and to determine whether hepatic microsomal P450 enzymes (including CYP2A5) are essential for the DCBN toxicity, by comparing the extents of DCBN toxicity between liver-Cpr-null (LCN) mice, which have little P450 activity in hepatocytes, and WT mice. We show that the loss of CYP2A5 expression did not alter systemic clearance of DCBN (at 25 mg/kg); but it did inhibit DCBN-induced non-protein thiol depletion and cytotoxicity in the OM. Thus, CYP2A5 plays an essential role in mediating DCBN toxicity in the OM. In contrast to the results seen in the Cyp2a5-null mice, the rates of systemic DCBN clearance were substantially reduced, while the extents of DCBN-induced nasal toxicity were increased, rather than decreased, in the LCN mice, compared to WT mice. Therefore, hepatic P450 enzymes, although essential for DCBN clearance, are not necessary for DCBN-induced OM toxicity. Our findings form the basis for a mechanism-based approach to assessing the potential risks of DCBN nasal toxicity in humans.
authors.affiliation: Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, NY 12201, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Xie
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.forename: Melissa
authors.initials: M
authors.lastname: Behr
authors.forename: Cheng
authors.initials: C
authors.lastname: Fang
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Horii
authors.forename: Jun
authors.initials: J
authors.lastname: Gu
authors.forename: Kurunthachalam
authors.initials: K
authors.lastname: Kannan
authors.forename: Xinxin
authors.initials: X
authors.lastname: Ding
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism / Q000502:physiology*; D001711:Biotransformation / Q000187:drug effects / Q000502:physiology; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D004789:Enzyme Activation; D006540:Herbicides / Q000493:pharmacokinetics / Q000633:toxicity*; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D018345:Mice, Knockout; D009570:Nitriles / Q000493:pharmacokinetics / Q000633:toxicity*; D009831:Olfactory Mucosa / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology
chemical_list: D006540:Herbicides; D009570:Nitriles; D001189:Aryl Hydrocarbon Hydroxylases; C585520:Cyp2a5 protein, mouse; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; C055869:dichlobanil