کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
9018122 | 1128688 | 2005 | 8 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Platelet-activating factor acetylhydrolase: selective inhibition by potent n-alkyl methylphosphonofluoridates
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کلمات کلیدی
SARdiisopropyl fluorophosphateCPOIC50DFPED50PMSFDMSO - DMSOPesticide - آفت کشAChE - آهیOrganophosphorus - ارگانوفسفورacetylhydrolase - استیل هیدرولازAcetylcholinesterase - استیل کولین استرازDimethyl sulfoxide - دیمتیل سولفواکسیدStructure–activity relationship - رابطه ساختار-فعالیتPlatelet-activating factor - فاکتور فعال کننده پلاکتPhenylmethanesulfonyl fluoride - فنیل متیل سولفونیل فلورایدPAF - نیروی هوایی پاکستانchlorpyrifos oxon - کلرپیریفوس اکسون
موضوعات مرتبط
علوم زیستی و بیوفناوری
علوم محیط زیست
بهداشت، سم شناسی و جهش زایی
پیش نمایش صفحه اول مقاله
![عکس صفحه اول مقاله: Platelet-activating factor acetylhydrolase: selective inhibition by potent n-alkyl methylphosphonofluoridates Platelet-activating factor acetylhydrolase: selective inhibition by potent n-alkyl methylphosphonofluoridates](/preview/png/9018122.png)
چکیده انگلیسی
Platelet-activating factor (PAF) is a potent endogenous phospholipid modulator of diverse biological activities, including inflammation and shock. PAF levels are primarily regulated by PAF acetylhydrolases (PAF-AHs). These enzymes are candidate secondary targets of organophosphorus (OP) pesticides and related toxicants. Previously known OP inhibitors of other serine hydrolases were tested with PAF-AH from mouse brain and testes of established functional importance compared with the structurally different human plasma enzyme. Several key OP pesticides and their oxon metabolites were very poor inhibitors of mouse brain and human plasma PAF-AH in vitro but moderately active for mouse brain and blood PAF-AH in vivo (e.g., tribufos defoliant and profenofos insecticide, presumably following oxidative bioactivation). OP compounds were then designed for maximum in vitro potency and selectivity for mouse brain PAF-AH vs. acetylcholinesterase (AChE). Lead compounds were found in a series of benzodioxaphosphorin 2-oxides. Ultrahigh potency and selectivity were achieved with n-alkyl methylphosphonofluoridates (long-chain sarin analogs): mouse brain and testes IC50 ⤠5 nM for C8-C18 analogs and 0.1-0.6 nM for C13 and C14 compounds; human plasma IC50 ⤠2 nM for C13-C18 analogs. AChE inhibitory potency decreased as chain length increased with maximum brain PAF-AH/AChE selectivity (>3000-fold) for C13-C18 compounds. The toxicity of i.p.-administered PAF (LD50 ca. 0.5 mg/kg) was increased less than 2-fold by pretreatment with tribufos or the C13n-alkyl methylphosphonofluoridate. These studies with a mouse model indicate that PAF-AH is not a major secondary target of OP pesticide poisoning. The optimized PAF-AH inhibitors may facilitate investigations on other aspects of PAF metabolism and action.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Toxicology and Applied Pharmacology - Volume 205, Issue 2, 1 June 2005, Pages 149-156
Journal: Toxicology and Applied Pharmacology - Volume 205, Issue 2, 1 June 2005, Pages 149-156
نویسندگان
Gary B. Quistad, Karl J. Fisher, Sarah C. Owen, Rebecka Klintenberg, John E. Casida,