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Clinical Toxicology (Philadelphia, Pa.) May 2020Current therapeutic options for organophosphorus (OP) insecticide self-poisoning including atropine and oximes are inadequate and case fatality may exceed 20%. An OP...
Current therapeutic options for organophosphorus (OP) insecticide self-poisoning including atropine and oximes are inadequate and case fatality may exceed 20%. An OP hydrolase enzyme, OpdA, has been used for environmental cleansing of OP insecticides and prevented death in rat and non-human primate models of OP insecticide poisoning if given very quickly after exposure. We here tested OpdA's ability to break down OP insecticides in human serum and in clinically relevant minipig models of OP insecticide poisoning. Human serum was spiked with seven diverse WHO Class II OP insecticides (chlorpyrifos, quinalphos, diazinon, dimethoate, fenthion, phenthoate, and profenofos) and the effect of OpdA on degradation measured. The pharmacodynamic and clinical effects of OpdA treatment were studied in Gottingen minipigs orally poisoned with agricultural formulations of dimethoate EC40 or methyl parathion EC60; pharmacodynamic effects were also assessed in profenofos EC50-poisoned pigs. OpdA effectively hydrolysed OP insecticides in human serum, with rates varying from 856 (SD 44) down to 0.107 (SD 0.01) moles of substrate hydrolysed/mole of enzyme/sec (k) for quinalphos and phenthoate, respectively, although at rates 2-3 log orders less than found in buffered solution. It showed clinical benefit in minipig models, reducing the dose of noradrenaline required to sustain an adequate mean arterial pressure after dimethoate (mean 0.149 [SD 0.10] μg/kg/h vs. 1.07 [SD 0.77] μg/kg/h, < .0001) and methyl parathion (mean 0.077 [SD 0.08] μg/kg/h vs. 0.707 [SD 0.49] μg/kg/h, < .0001) poisoning. OpdA reduced blood OP insecticide concentration and acetylcholinesterase inhibition after poisoning by dimethoate, methyl parathion, and profenofos insecticides. incubation of OpdA in human serum showed hydrolysis of diverse OP insecticides, although at lower rates than found in buffer solutions. This activity results in clinical and pharmacodynamic efficacy against several OP insecticides. These results support the testing of OpdA in further animal models before considering human trials to determine whether it may become an urgently required novel therapeutic agent for OP insecticide self-poisoning.
Topics: Animals; Aryldialkylphosphatase; Disease Models, Animal; Humans; Insecticides; Methyl Parathion; Organophosphate Poisoning; Swine; Swine, Miniature
PubMed: 31452424
DOI: 10.1080/15563650.2019.1655149 -
Toxicology Letters Oct 2019Organophosphates are chemical pollutants that are existed widely in the environment, but the reactions of these agents with blood proteins are still not fully clarified....
Organophosphates are chemical pollutants that are existed widely in the environment, but the reactions of these agents with blood proteins are still not fully clarified. The current story was to analyze the static and dynamic interactions between human serum albumin (HSA) and phenthoate and then uncover the impact of the conjugations on the acetylcholinesterase (AChE) activity at the microscopic scale. Experimental results revealed clearly that the bioconjugate of the HSA-phenthoate was yielded and the conformation of HSA can produce autoregulation during the reaction. Dynamic reaction processes suggested that the conformational flexibility of the specific protein domain was changed significantly in equilibrium, and the electrostatic interaction energy played a major role in total energy of the biosystems, which matches the results of wet experiment and molecular docking. We also found that the modes of homologous proteins-phenthoate have obvious distinctions, and this point is related closely to the local dynamic flexibility of biomolecular structures. Additionally, the degree of bioconjugation of the HSA-phenthoate is positively associated with the enzymatic activity of target AChE, which may be attributed to the competitive reactions between HSA and AChE. Evidently, this scenario could provide useful molecular information for the systematic exploration of the toxicokinetics of organophosphorus compounds.
Topics: Acetylcholinesterase; Binding Sites; Binding, Competitive; Cholinesterase Inhibitors; Humans; Insecticides; Models, Biological; Molecular Docking Simulation; Organothiophosphorus Compounds; Protein Binding; Protein Conformation; Protein Domains; Serum Albumin, Human
PubMed: 31362050
DOI: 10.1016/j.toxlet.2019.07.025