Author Report for: Sparks SENo contact information in database for Sparks SE
Quistad GB, Barlow C, Winrow CJ, Sparks SE, Casida JE Ref: Proc Natl Acad Sci U S A, 100:7983, 2003 : PubMed ESTHER: Quistad_2003_Proc.Natl.Acad.Sci.U.S.A_100_7983 PubMedSearch: Quistad 2003 Proc.Natl.Acad.Sci.U.S.A 100 7983 PubMedID: 12805562 Abstract Neuropathy target esterase (NTE) is inhibited by several organophosphorus (OP) pesticides, chemical warfare agents, lubricants, and plasticizers, leading to OP-induced delayed neuropathy in people (>30,000 cases of human paralysis) and hens (the best animal model for this demyelinating disease). The active site region of NTE as a recombinant protein preferentially hydrolyzes lysolecithin, suggesting that this enzyme may be a type of lysophospholipase (LysoPLA) with lysolecithin as its physiological substrate. This hypothesis is tested here in mouse brain by replacing the phenyl valerate substrate of the standard NTE assay with lysolecithin for an "NTE-LysoPLA" assay with four important findings. First, NTE-LysoPLA activity, as the NTE activity, is 41-45% lower in Nte-haploinsufficient transgenic mice than in their wild-type littermates. Second, the potency of six delayed neurotoxicants or toxicants as in vitro inhibitors varies from IC50 0.02 to 13,000 nM and is essentially the same for NTE-LysoPLA and NTE (r2 = 0.98). Third, the same six delayed toxicants administered i.p. to mice at multiple doses inhibit brain NTE-LysoPLA and NTE to the same extent (r2 = 0.90). Finally, their in vivo inhibition of brain NTE-LysoPLA generally correlates with delayed toxicity. Therefore, OP-induced delayed toxicity in mice, and possibly the hyperactivity associated with NTE deficiency, may be due to NTE-LysoPLA inhibition, leading to localized accumulation of lysolecithin, a known demyelinating agent and receptor-mediated signal transducer. This mouse model has some features in common with OP-induced delayed neuropathy in hens and people but differs in the neuropathological signs and apparently the requirement for NTE aging. Title: Major intermediates in organophosphate synthesis (PCl3, POCl3, PSCl3, and their diethyl esters) are anticholinesterase agents directly or on activation Segall Y, Quistad GB, Sparks SE, Casida JE Ref: Chemical Research in Toxicology, 16:350, 2003 : PubMed ESTHER: Segall_2003_Chem.Res.Toxicol_16_350 PubMedSearch: Segall 2003 Chem.Res.Toxicol 16 350 PubMedID: 12641435 Abstract Three phosphotrichlorides [phosphorus trichloride (PCl(3)), phosphorus oxychloride (POCl(3)), and thiophosphoryl chloride (PSCl(3))] with an annual U.S. production of >500,000,000 pounds and their diethyl esters are intermediates in the production of organophosphorus pesticides, plastics, flame retardants, and hydraulic fluids. They are classified as highly toxic to mammals based on acute oral and inhalation data with rats. This study considers their mechanisms of toxicity. PCl(3) and POCl(3) inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) from several species with in vitro IC(50) values of 5-36 and 88-1200 microM, respectively; PSCl(3) is a less potent inhibitor. These phosphotrichlorides have high vapor toxicity to houseflies with in vivo inhibition of brain AChE activity correlating with mortality. PCl(3) and POCl(3) produce cholinergic poisoning signs on ip administration to mice, and all three phosphotrichlorides give marked in vivo inhibition of serum BChE but not brain AChE activity. PCl(3) is a direct acting AChE inhibitor. Our earlier proposed activation of POCl(3) is confirmed here by preparing pure Cl(2)P(O)OH and its potassium and dicyclohexylamine salts that reproduce the action of POCl(3) as in vitro AChE inhibitors and toxicants in mice. PSCl(3) on hydrolysis yields Cl(2)P(O)SH [which oxidizes with peracid to Cl(2)P(O)SOH] as the proposed activation product. Vapors of (EtO)(2)PCl, (EtO)(2)P(O)Cl, and (EtO)(2)P(S)Cl are lethal to houseflies as in vivo AChE inhibitors, the first two acting directly and the last one on oxidative activation to (EtO)(2)P(O)Cl (possibly by P450) or (EtO)(2)P(O)SCl (a phosphorylating agent in a peracid oxidation system). Thus PCl(3), (EtO)(2)PCl, and (EtO)(2)P(O)Cl act directly as AChE inhibitors whereas POCl(3) and PSCl(3) undergo hydrolytic activation and (EtO)(2)P(S)Cl undergoes oxidative activation. In contrast, the toxicity to mice of phosphofluorides [FP(O)Cl(2), F(Cl)P(O)OH, and F(2)P(O)OH; studied as model compounds for comparison] may be due to liberating fluoride ion. Title: Toxicological and structural features of organophosphorus and organosulfur cannabinoid CB1 receptor ligands Segall Y, Quistad GB, Sparks SE, Nomura DK, Casida JE Ref: Toxicol Sci, 76:131, 2003 : PubMed ESTHER: Segall_2003_Toxicol.Sci_76_131 PubMedSearch: Segall 2003 Toxicol.Sci 76 131 PubMedID: 12944586 Inhibitor(s) related to this paper: DSF Abstract Potent cannabinoid CB1 receptor ligands include anandamide [N-(2-hydroxyethyl)arachidonamide], Delta9-tetrahydrocannabinol, and 3H-CP 55,940 at the agonist site and selected organophosphorus esters (including some pesticides) and organosulfur compounds at a proposed closely coupled "nucleophilic" site. This study considers the toxicological and structural features of alkylfluorophosphonates, benzodioxaphosphorin oxides, alkanesulfonyl fluorides, and analogs acting at the nucleophilic site. Binding at the agonist site, using3H-CP 55,940 in assays with mouse brain membranes, is inhibited byO-isopropyl dodecylfluorophosphonate (compound 2), dodecanesulfonyl fluoride (compound 14) and dodecylbenzodioxaphosphorin oxide with IC50 values of 2-11 nM. Compounds 2 and 14 are also effectivein vivo, with 84% inhibition of mouse brain CB1 binding 4 h after intraperitoneal dosage at 30 mg/kg. Compound 14-inhibited CB1 in mouse brain requires about 3-4 days for recovery of 50% activity, suggesting covalent derivatization. Delayed toxicity (mortality in 0.3-5 days) from compounds 2, 14, and octanesulfonyl fluoride (18) is more closely associated with in vivo inhibition of brain neuropathy target esterase-lysophospholipase (NTE-LysoPLA) than with that of CB1 or acetylcholinesterase. NTE-LysoPLA inhibited by sulfonyl fluorides 14 and 18 cannot "age," a proposed requirement for NTE phosphorylated by organophosphorus-delayed neurotoxicants. Several octane- and dodecanesulfonamides with N-(2-hydroxyethyl) and other substituents based on anandamide give depressed mobility and recumbent posture in mice, but the effects do not correlate with potency for CB1 inhibition in vitro. Specific toxicological responses are not clearly associated with organophosphorus- or organosulfur-induced inhibition of the proposed CB1 nucleophilic site in mouse brain. On the other hand, the most potent CB1 inhibitors examined here are also NTE-LysoPLA inhibitors and cause delayed toxicity in mice. Title: Selective inhibitors of fatty acid amide hydrolase relative to neuropathy target esterase and acetylcholinesterase: toxicological implications Quistad GB, Sparks SE, Segall Y, Nomura DK, Casida JE Ref: Toxicol Appl Pharmacol, 179:57, 2002 : PubMed ESTHER: Quistad_2002_Toxicol.Appl.Pharmacol_179_57 PubMedSearch: Quistad 2002 Toxicol.Appl.Pharmacol 179 57 PubMedID: 11884237 Inhibitor(s) related to this paper: Tribufos Abstract Fatty acid amide hydrolase (FAAH) plays an important role in nerve function by regulating the action of endocannabinoids (e.g., anandamide) and hydrolyzing a sleep-inducing factor (oleamide). Several organophosphorus pesticides and related compounds are shown in this study to be more potent in vivo inhibitors of mouse brain FAAH than neuropathy target esterase (NTE), raising the question of the potential toxicological relevance of FAAH inhibition. These FAAH-selective compounds include tribufos and (R)-octylbenzodioxaphosphorin oxide with delayed neurotoxic effects in mice and hens plus several organophosphorus pesticides (e.g., fenthion) implicated as delayed neurotoxicants in humans. The search for a highly potent and selective inhibitor for FAAH relative to NTE for use as a toxicological probe culminated in the discovery that octylsulfonyl fluoride inhibits FAAH by 50% at 2 nM in vitro and 0.2 mg/kg in vivo and NTE is at least 100-fold less sensitive in each case. More generally, the studies revealed 12 selective in vitro inhibitors for FAAH (mostly octylsulfonyl and octylphosphonyl derivatives) and 9 for NTE (mostly benzodioxaphosphorin oxides and organophosphorus fluoridates). The overall in vivo findings with 16 compounds indicate the expected association of AChE inhibition with acute or cholinergic syndrome and >70% brain NTE inhibition with delayed neurotoxic action. Surprisingly, 75-99% brain FAAH inhibition does not lead to any overt neurotoxicity or change in behavior (other than potentiation of exogenous anandamide action). Thus, FAAH inhibition in mouse brain does not appear to be a primary target for organophosphorus pesticide-induced neurotoxic action (cholinergic or intermediate syndrome or delayed neurotoxicity). Title: Cannabinoid CB1 receptor as a target for chlorpyrifos oxon and other organophosphorus pesticides Quistad GB, Nomura DK, Sparks SE, Segall Y, Casida JE Ref: Toxicol Lett, 135:89, 2002 : PubMed ESTHER: Quistad_2002_Toxicol.Lett_135_89 PubMedSearch: Quistad 2002 Toxicol.Lett 135 89 PubMedID: 12243867 Inhibitor(s) related to this paper: Tribufos Abstract Binding of the endocannabinoid anandamide or of Delta(9)-tetrahydrocannabinol to the agonist site of the cannabinoid receptor (CB1) is commonly assayed with [3H]CP 55,940. Potent long-chain alkylfluorophosphonate inhibitors of agonist binding suggest an additional, important and closely-coupled nucleophilic site, possibly undergoing phosphorylation. We find that the CB1 receptor is also sensitive to inhibition in vitro and in vivo by several organophosphorus pesticides and analogs. Binding of [3H]CP 55,940 to mouse brain CB1 receptor in vitro is inhibited 50% by chlorpyrifos oxon at 14 nM, chlorpyrifos methyl oxon at 64 nM and paraoxon, diazoxon and dichlorvos at 1200-4200 nM. Some 15 other organophosphorus pesticides and analogs are less active in vitro. The plant defoliant tribufos inhibits CB1 in vivo, without cholinergic poisoning signs, by 50% at 50 mg/kg intraperitoneally with a recovery half-time of 3-4 days, indicating covalent derivatization. [3H-ethyl]Chlorpyrifos oxon may be suitable for radiolabeling and characterization of this proposed nucleophilic site. Title: Fatty acid amide hydrolase inhibition by neurotoxic organophosphorus pesticides Quistad GB, Sparks SE, Casida JE Ref: Toxicol Appl Pharmacol, 173:48, 2001 : PubMed ESTHER: Quistad_2001_Toxicol.Appl.Pharmacol_173_48 PubMedSearch: Quistad 2001 Toxicol.Appl.Pharmacol 173 48 PubMedID: 11350214 Inhibitor(s) related to this paper: EOPF, Tribufos Abstract Organophosphorus (OP) compound-induced inhibition of acetylcholinesterase (AChE) and neuropathy target esterase explains the rapid onset and delayed neurotoxic effects, respectively, for OP insecticides and related compounds but apparently not a third or intermediate syndrome with delayed onset and reduced limb mobility. This investigation tests the hypothesis that fatty acid amide hydrolase (FAAH), a modulator of endogenous signaling compounds affecting sleep (oleamide) and analgesia (anandamide), is a sensitive target for OP pesticides with possible secondary neurotoxicity. Chlorpyrifos oxon inhibits 50% of the FAAH activity (IC50 at 15 min, 25 degrees C, pH 9.0) in vitro at 40--56 nM for mouse brain and liver, whereas methyl arachidonyl phosphonofluoridate, ethyl octylphosphonofluoridate (EOPF), oleyl-4H-1,3,2-benzodioxaphosphorin 2-oxide (oleyl-BDPO), and dodecyl-BDPO give IC50s of 0.08--1.1 nM. These BDPOs and EOPF inhibit mouse brain FAAH in vitro with > or =200-fold higher potency than for AChE. Five OP pesticides inhibit 50% of the brain FAAH activity (ED50) at <30 mg/kg 4 h after ip administration to mice; while inhibition by chlorpyrifos, diazinon, and methamidophos occurs near acutely toxic levels, profenofos and tribufos are effective at asymptomatic doses. Two BDPOs (dodecyl and phenyl) and EOPF are potent inhibitors of FAAH in vivo (ED50 0.5--6 mg/kg). FAAH inhibition of > or =76% in brain depresses movement of mice administered anandamide at 30 mg/kg ip, often leading to limb recumbency. Thus, OP pesticides and related inhibitors of FAAH potentiate the cannabinoid activity of anandamide in mice. More generally, OP compound-induced FAAH inhibition and the associated anandamide accumulation may lead to reduced limb mobility as a secondary neurotoxic effect. Title: Phosphoacetylcholinesterase: toxicity of phosphorus oxychloride to mammals and insects that can be attributed to selective phosphorylation of acetylcholinesterase by phosphorodichloridic acid Quistad GB, Zhang N, Sparks SE, Casida JE Ref: Chemical Research in Toxicology, 13:652, 2000 : PubMed ESTHER: Quistad_2000_Chem.Res.Toxicol_13_652 PubMedSearch: Quistad 2000 Chem.Res.Toxicol 13 652 PubMedID: 10898598 Abstract Phosphorus oxychloride (POCl(3)) is an intermediate in the synthesis of many organophosphorus insecticides and chemical warfare nerve gases that are toxic to insects and mammals by inhibition of acetylcholinesterase (AChE) activity. It was therefore surprising to observe that POCl(3), which is hydrolytically unstable, also itself gives poisoning signs in ip-treated mice and fumigant-exposed houseflies similar to those produced by the organophosphorus ester insecticides and chemical warfare agents. In mice, POCl(3) inhibits serum butyrylcholinesterase (BuChE) at a sublethal dose and muscle but not brain AChE at a lethal dose. In houseflies, POCl(3)-induced brain AChE inhibition is correlated with poisoning and the probable cause thereof. POCl(3) in vitro is selective for AChE (IC(50) = 12-36 microM) compared with several other serine hydrolases (BuChE, carboxylesterase, elastase, alpha-chymotrypsin, and thrombin) (IC(50) = 88-2000 microM). With electric eel AChE, methylcarbamoylation of the active site with eserine reversibly protects against subsequent irreversible inhibition by POCl(3). Most importantly, POCl(3)-induced electric eel AChE inhibition prevents postlabeling with [(3)H]diisopropyl phosphorofluoridate; i.e., both compounds phosphorylate at Ser-200 in the catalytic triad. Pyridine-2-aldoxime methiodide does not reactivate POCl(3)-inhibited AChE, consistent with an anionic phosphoserine residue at the esteratic site. The actual phosphorylating agent is formed within seconds from POCl(3) in water, has a half-life of approximately 2 min, and is identified as phosphorodichloridic acid [HOP(O)Cl(2)] by (31)P NMR and derivatization with dimethylamine to HOP(O)(NMe(2))(2). POCl(3) on reaction with water and HOP(O)Cl(2) have the same potency for inhibition of AChE from either electric eel or housefly head as well as the same toxicity for mice. In summary, the acute toxicity of POCl(3) is attributable to hydrolytic activation to HOP(O)Cl(2) that phosphorylates AChE at the active site to form enzymatically inactive [O-phosphoserine]AChE. Title: Organophosphorus pesticide-induced butyrylcholinesterase inhibition and potentiation of succinylcholine toxicity in mice Sparks SE, Quistad GB, Casida JE Ref: J Biochem Mol Toxicol, 13:113, 1999 : PubMed ESTHER: Sparks_1999_J.Biochem.Mol.Toxicol_13_113 PubMedSearch: Sparks 1999 J.Biochem.Mol.Toxicol 13 113 PubMedID: 9890196 Inhibitor(s) related to this paper: Chlorpyrifos, Ethephon, Methamidophos, Phenyl-saligenin-phosphate~PSP, Profenofos, Tribufos Abstract Succinylcholine is the most important rapid-acting depolarizing muscle relaxant during anesthesia. Its desirable short duration of action is controlled by butyrylcholinesterase, the detoxifying enzyme. There are two reported cases of prolonged paralysis from succinylcholine in patients poisoned with the organophosphorus insecticides parathion and chlorpyrifos. The present study examines the possibility that other organophosphorus and methylcarbamate pesticides might also prolong succinylcholine action by inhibiting butyrylcholinesterase using mice treated intraperitoneally as a model and relating inhibition of blood serum hydrolysis of butyrylthiocholine to potentiated toxicity (mouse mortality). The organophosphorus plant defoliant tribufos (4 h pretreatment, 160 mg/kg) and organophosphorus plant growth regulator ethephon (1 h pretreatment, 200 mg/kg) potentiate the toxicity of succinylcholine by seven- and fourfold, respectively. Some other pesticides or analogs are more potent sensitizers for succinylcholine toxicity with threshold levels of 0.5, 1.0, 1.7, 8, 10, and 67 mg/kg for phenyl saligenin cyclic phosphonate, profenofos, methamidophos, tribufos, chlorpyrifos, and ethephon, respectively. Enhanced mortality from succinylcholine is generally observed when serum butyrylcholinesterase is inhibited 55-94%. Mivacurium, a related nondepolarizing muscle relaxant also detoxified by butyrylcholinesterase, is likewise potentiated by at least threefold on 4 hour pretreatment with tribufos (25 mg/kg) or profenofos (10 mg/kg). Title: S-methylation as a bioactivation mechanism for mono- and dithiocarbamate pesticides as aldehyde dehydrogenase inhibitors Staub RE, Sparks SE, Quistad GB, Casida JE Ref: Chemical Research in Toxicology, 8:1063, 1995 : PubMed ESTHER: Staub_1995_Chem.Res.Toxicol_8_1063 PubMedSearch: Staub 1995 Chem.Res.Toxicol 8 1063 PubMedID: 8605289 Abstract S-Methylation is a new bioactivation mechanism for metam and metabolites of methyl isothiocyanate and dazomet in mice. These soil fumigants are converted to S-methyl metam [MeNHC(S)SMe] which reaches peak levels in liver, kidney, brain, and blood 10-20 min after intraperitoneal (ip) treatment. The half-life of S-methyl metam administered ip is 8-12 min in each of these tissues. S-Methyl metam-oxon [MeNHC(O)SMe] is also detected as a metabolite of each of these soil fumigants on analysis by gas chromatography/mass spectrometry with chemical ionization. The conversion of methyl isothiocyanate to S-methyl metam and its oxon probably involves conjugation with glutathione, hydrolysis to S-(N-methylthiocarbamoyl)-cysteine, cleavage by cysteine conjugate beta-lyase to release metam, and finally methylation and oxidative desulfuration. Metam and dazomet are converted to S-methyl metam by mouse liver microsomes on fortification with S-adenosylmethionine. Metam, methyl isothiocyanate, dazomet, and three metabolites (metam-oxon [MeNHC(O)SH], MeNHC(S)SMe, and MeNHC-(O)SMe) administered ip to mice at 40 mg/kg inhibit low-Km liver mitochondrial aldehyde dehydrogenase and elevate ethanol-dependent blood and brain acetaldehyde levels. Several fungicides including the dialkyldithiocarbamates as the disulfide (thiram and the related alcohol-abuse drug disulfiram) and metal salts (ziram) also yield S-methyl thiocarbamate metabolites. Eight S-alkyl and S-(chloroallyl) thiocarbamate herbicides (EPTC, molinate, butylate, vernolate, pebulate, diallate, sulfallate, and triallate), but not their S-chlorobenzyl analog (thiobencarb), undergo sequential liberation of the thiocarbamic acid and then S-methylation, forming the S-methyl thiocarbamates which are new metabolites and potential aldehyde dehydrogenase inhibitors. The S-methyl mono- and dithiocarbamate metabolites of these herbicides and fungicides are easily identified by retention time on gas chromatography and by mass spectrometry giving [MH]+ plus [R1R2NCO]+ or [R1R2NCS]+, respectively, as the two major ions. | |||||||
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