Organophosphorus EsterInduced Chronic …：有机磷酯诱导的慢性… .ppt

Organphosphorus Compounds-Induced NeurotoxicityOrganophosphorus compounds Used in medicine,industry,agriculture and as warfare agents.Have a wide range of acute toxicity:a)low acute toxicity chemicals such as tricresyl phosphates(TCPs)b)highly toxic nerve agents such as sarin,soman and tabun.Actions of Organophosphorus Compounds1.Cholinergic Neurotoxicity2.Organophosphorus Ester-Induced Neurotoxicity(OPIDN)3.Organophosphorus Ester-Induced Chronic Neurotoxicity(OPICN)1.Cholinergic NeurotoxicityInhibition of Acetylcholinesterase(AChE),an enzyme essential for lifeORGANOPHOSPHATEPOOOOXR Organophosphate+dR(a)(b)(d)(c)phe 297phe 295acyl pocket(a)(b)(d)(c)phe 297phe 295acyl pocketPeripheral binding site(a)(b)(d)(c)phe 297phe 295acyl pocketPeripheral binding siteManifestations of Organophosphate PoisoningOptic SystemPupil ConstrictionBlurred VisionLacrimationRespiratory SystemBronchospasmBronchial SecretionPulmonary EdemaTightness of ChestWheezingCoughDifficulty BreathingGastrointestinal TractSalivationNauseaCrampsAbdominal PainVomitingDiarrheaFecal IncontinenceUrinary-GenitalUrinary IncontinenceImpotenceUterus ContractionBrainHeadacheDizzinessVertigoAnxietyApathyConfusionAnorexiaInsomniaLethargyFatigueInability to ConcentrateMemory ImpairmentConvulsionComaCardiovascular SystemTachycardiaIncreased Blood PressureMusculatureWeaknessTremorFasciculationsTwitchingCrampsIncreased SweatingTreatment of Cholinergic Toxicity1.2-PAM(2-pyridine aldoxime methiodide)hydrolyzes phosphorylated enzyme thus accelerating the regeneration of active AChE;should be administered rapidly within 10 to 15 minutes of exposure,before AChE aging.2.Atropine,an antagonist of muscarinic ACh receptor(AChR)3.Shielding of AChEOrganophosphorus nerve agents,such as sarin act by irreversibly inhibiting AChE in the peripheral and central nervous systems.2.Pyridostigmine Bromide(PB)is administered to protect against toxicity.PB is approved by the FDA for soman.3.Prophylaxis Principle is that PB acts by shielding AChE in peripheral nervous system to reversibly inhibit 30-40%of the enzyme,protecting it from permanent inhibition by the nerve gas.4.Enzyme activity is restored following spontaneous decarbamyalation of the AChE.Result Free enzyme and near-normal neuromuscular an autonomic functions.4.Bioscavengers 1.Butyrylcholinesterase(BChE)is a naturally occurring enzyme in blood.2.Its blood concentration is 2 mg/liter.3.BChE has no known function;however,it functions as the first line of defense against poisoning with organphosphorus compounds.4.It acts as a bioscavenger,like a sponge to absorb and degrade organphosphorus compounds(e.g.,nerve agents and insecticides).Recombinant BChE(rBCHE)1.Recombinant human BChE(rBChE)is being developed under the trade name Protexia as a pre-and post-exposure therapy for organphosphorus compound poisoning.2.Protexia is a pegylated rBChE,that is formed by conjugation of the rBChE with polyethylene glycol in order to:1.Decrease rBChE immunogenicity2.Increase rBChE stability 3.Increase circulating serum of rBChE3.A limited human study of Protexia has started.2.OPIDNOPIDN is a neurodegenerative disorder:1.A latent period;6 and 14 days.2.Neuropathological lesions:medulla of the brain,spinal cord,and sciatic nerve.3.Degeneration of the axon and of myelin 4.Species and age sensitivity.5.Inhibition of neurotoxicity target esterase(NTE).POCl3OHPOOOOCH3CH3CH3CH3+3TOCPPhosphorus oxychlorideTri-ortho-cresyl phosphateSynthetic pathways of TOCPTCPsOHCH3OHCH3OHCH3OPOOOCH3CH3CH3+POCL3+POCL3+POCL3OPOOOCH3CH3CH3OPOOOCH3CH3CH3ortho-cresolmeta-cresolpara-cresolTOCPTMCPTPCP Uses of Tricresyl Phosphates TCPs 1.Antiwear and additive in synthetic lubricants.2.Flame retardant3.Plasticizer Neurotoxity of TCPs1.TOCP is a weak inhibitor of AChE2.It is a potent producer of OPIDN3.Other isomers have not been thoroughly tested for OPIDN Isomers of Tri-cresyl Phosphate(TCP)There are 10 possible TCP structures:Isomers OPIDNo,o,o +o,o,m;o,o,p +o,m,m,;o,m,p;o,p,p +m,m,m;m,m,p;m,p,p;p,p,p -Chronology of TOCP-Induced OPIDNYear Country Incidence Cases1899 France Creosote 591930 USA Contaminated Ginger Extract Approx.50,0001925-1934 France,Germany,Apiol Abortfacient 200-500 Switzerland1937 South Africa Contaminated Cooking Oil 6001940 Switzerland Contaminated Cooking oil 801942 Britain Manufacturing 31945 Britain Contaminated Cottonseed Oil 171943-1947 Germany Used as cooking oil 10-201947 Switzerland Contaminated food 731952 Switzerland Contaminated Olive Oil 801955 South Africa Contaminated Water 111959 Morocco Used as cooking Oil 10,0001960 India Contaminated Cooking Oil 581966 Rumania Contaminated Alcohol 121967 Fiji Islands Contaminated Flower1973 Morocco Shoe Glue Exposure 401977-1978 Sri Lanka Contaminated Sesame Oil 231988 India Contaminated Cooking Oil 2 Neurological dysfunction of OPIDN1.Latent period:Days to weeks2.Progressive phase:Symmetric cramping,numbness and tingling in feet and legs,bilateral dragging of toes(foot-drop),flaccid paralysis.3.S