Mechanisms of olfactory toxicity of the herbicide 2,6-dichlorobenzonitrile: Essential roles of CYP2A5 and target-tissue metabolic activation

Fang Xie, Xin Zhou, Melissa Behr, Cheng Fang, Yuichi Horii, Jun Gu, Kurunthachalam Kannan, Xinxin Ding

Research output: Contribution to journalArticle

20 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)101-106
Number of pages6
JournalToxicology and Applied Pharmacology
Volume249
Issue number1
DOIs
StatePublished - Nov 15 2010
Externally publishedYes

Fingerprint

Herbicides
Olfactory Mucosa
Toxicity
Chemical activation
Tissue
Cytochrome P-450 Enzyme System
Liver
Nose
Sulfhydryl Compounds
dichlobanil
Metabolic Activation
Hepatocytes
Cytotoxicity
Mucous Membrane

Keywords

  • CYP2A5
  • Cytochrome P450
  • Dichlobenil
  • Gene knockout
  • Nasal toxicity
  • Olfactory mucosa

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Cite this

Mechanisms of olfactory toxicity of the herbicide 2,6-dichlorobenzonitrile : Essential roles of CYP2A5 and target-tissue metabolic activation. / Xie, Fang; Zhou, Xin; Behr, Melissa; Fang, Cheng; Horii, Yuichi; Gu, Jun; Kannan, Kurunthachalam; Ding, Xinxin.

In: Toxicology and Applied Pharmacology, Vol. 249, No. 1, 15.11.2010, p. 101-106.

Research output: Contribution to journalArticle

Xie, Fang ; Zhou, Xin ; Behr, Melissa ; Fang, Cheng ; Horii, Yuichi ; Gu, Jun ; Kannan, Kurunthachalam ; Ding, Xinxin. / Mechanisms of olfactory toxicity of the herbicide 2,6-dichlorobenzonitrile : Essential roles of CYP2A5 and target-tissue metabolic activation. In: Toxicology and Applied Pharmacology. 2010 ; Vol. 249, No. 1. pp. 101-106.
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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.",
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AU - Zhou, Xin

AU - Behr, Melissa

AU - Fang, Cheng

AU - Horii, Yuichi

AU - Gu, Jun

AU - Kannan, Kurunthachalam

AU - Ding, Xinxin

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AB - 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.

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