کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2570042 | 1128564 | 2010 | 6 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Mechanisms of olfactory toxicity of the herbicide 2,6-dichlorobenzonitrile: Essential roles of CYP2A5 and target-tissue metabolic activation
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کلمات کلیدی
CmaxP450 or CYPCYP2A5GSHLCNtmaxAUC - AUCNADPH-cytochrome P450 reductase - NADPH-cytochrome P450 ردوکتازt1/2 - t1 / 2CPR - احیای قلبی ریویmaximum plasma concentration - حداکثر غلظت پلاسماdichlobenil - دی کلوبنیلCytochrome P450 - سیتوکروم پی۴۵۰Mass spectrometry - طیف سنجی جرمیOlfactory mucosa - مخاط بینیNasal toxicity - مسمومیت بینیArea under the concentration-time curve - منطقه تحت منحنی غلظت-زمانGene knockout - نابودی ژنwild-type - نوع وحشیreduced glutathione - کاهش گلوتاتیونhigh-performance liquid chromatography - کروماتوگرافی مایعی کاراHPLC - کروماتوگرافی مایعی کاراGas chromatography - کروماتوگرافی گازی
موضوعات مرتبط
علوم زیستی و بیوفناوری
علوم محیط زیست
بهداشت، سم شناسی و جهش زایی
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چکیده انگلیسی
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 25Â 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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Toxicology and Applied Pharmacology - Volume 249, Issue 1, 15 November 2010, Pages 101-106
Journal: Toxicology and Applied Pharmacology - Volume 249, Issue 1, 15 November 2010, Pages 101-106
نویسندگان
Fang Xie, Xin Zhou, Melissa Behr, Cheng Fang, Yuichi Horii, Jun Gu, Kurunthachalam Kannan, Xinxin Ding,