Lowering of IOP by Echothiophate Iodide in Pseudophakic Eyes with Glaucoma

Kg, Schmidt; Horowitz, Yosefa; Buckman, Gila; Segev, Eitan; Levinger, E.; Geyer, Orna

doi:10.3109/02713681003794076

Cited by 10 publications

(3 citation statements)

References 6 publications

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“…Among them, P-S bonded phosphoro-and phosphono-thioates are of interest (Scheme 1). For example, echothiophate (phospholine iodide) is a drug used for treatment of glaucoma [3], malathion (carbophos) is an agriculture pesticide for eradication of mosquitos also used for treatment of pediculosis [4,5], and VX is a potent chemical warfare nerve agent [6]. Spontaneous hydrolysis or enzyme-catalyzed hydrolysis of phosphoro/phosphono-thioates and phosphylation of ChEs by these compounds results in breakage of the P-S bond in the P-S-alkyl chain with release of thiol leaving group.…”

Section: Introductionmentioning

confidence: 99%

Steady-State Kinetics of Enzyme-Catalyzed Hydrolysis of Echothiophate, a P–S Bonded Organophosphorus as Monitored by Spectrofluorimetry

et al. 2020

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Enzyme-catalyzed hydrolysis of echothiophate, a P–S bonded organophosphorus (OP) model, was spectrofluorimetrically monitored, using Calbiochem Probe IV as the thiol reagent. OP hydrolases were: the G117H mutant of human butyrylcholinesterase capable of hydrolyzing OPs, and a multiple mutant of Brevundimonas diminuta phosphotriesterase, GG1, designed to hydrolyze a large spectrum of OPs at high rate, including V agents. Molecular modeling of interaction between Probe IV and OP hydrolases (G117H butyrylcholinesterase, GG1, wild types of Brevundimonas diminuta and Sulfolobus solfataricus phosphotriesterases, and human paraoxonase-1) was performed. The high sensitivity of the method allowed steady-state kinetic analysis of echothiophate hydrolysis by highly purified G117H butyrylcholinesterase concentration as low as 0.85 nM. Hydrolysis was michaelian with Km = 0.20 ± 0.03 mM and kcat = 5.4 ± 1.6 min−1. The GG1 phosphotriesterase hydrolyzed echothiophate with a high efficiency (Km = 2.6 ± 0.2 mM; kcat = 53400 min−1). With a kcat/Km = (2.6 ± 1.6) × 107 M−1min−1, GG1 fulfills the required condition of potential catalytic bioscavengers. quantum mechanics/molecular mechanics (QM/MM) and molecular docking indicate that Probe IV does not interact significantly with the selected phosphotriesterases. Moreover, results on G117H mutant show that Probe IV does not inhibit butyrylcholinesterase. Therefore, Probe IV can be recommended for monitoring hydrolysis of P–S bonded OPs by thiol-free OP hydrolases.

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Section: Introductionmentioning

confidence: 99%

Steady-State Kinetics of Enzyme-Catalyzed Hydrolysis of Echothiophate, a P–S Bonded Organophosphorus as Monitored by Spectrofluorimetry

et al. 2020

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Section: Introductionmentioning

confidence: 99%

“…These compounds are commercially used in the market for local and industrial purposes. Besides, they are used as a therapeutic agent for the treatment of ophthalmic cases (Schmidt et al, 2010), as antihelmintics against parasites (Almeida et al, 2010) or as nerve agents in chemical warfare (Bajgar et al, 2009). Human paraoxonase 1 (PON1) is an essential and critical enzyme that is synthesized mostly in the liver and secreted into the blood in humans and animals.…”

Section: Introductionmentioning

confidence: 99%

Effect of paraoxonase 1 192 Q/R polymorphism on paraoxonase and acetylcholinesterase enzyme activities in a Turkish population exposed to organophosphate

et al. 2013

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Organophosphate (OP) compounds are the most commonly used pesticide groups and they are commercially used in the market for local and industrial purposes. Paraoxonase 1 (PON1) enzyme plays an important role in biotransformation of OP compounds, which shows toxic effects via inhibiting the acetylcholinesterase (AChE). The aim of this study was to determine the effects of PON1 gene polymorphism and its effects on PON and AChE enzyme activities in individuals who were exposed to organophosphorus insecticides due to occupational reasons, and to profile the probability of susceptibility to organophosphorus compounds. For this purpose, 54 individuals who were exposed to OPs and 54 healthy unrelated controls were studied. First, PON1 and AChE enzyme activities were measured. Second, PON1 192 Q/R polymorphism was determined by standard polymerase chain reaction-restriction fragment length polymorphism technique. When the PON1 192 Q/R polymorphism was compared with PON1 enzyme activities, statistically significant association was found in both OP-exposed and control groups (p < 0.05). PON1 192 R(+) (QR + RR genotypes) genotype carriers had higher PON1 activities than 192 R(-) (QQ) genotype carriers. On the other hand, results were statistically analyzed in terms of AChE enzyme activities and there were statistically significant differences only in the OP-exposed group (p < 0.05). The mean AChE concentration in the OP-exposed group was determined as 33.79 ± 6.84 U/g haemoglobin (Hb) for PON1 192 R(+) carriers and 30.37 ± 7.62 U/g Hb for PON1 192 R(+) carriers. As a conclusion, PON1 and AChE activities were increasing according to the genotypes found in individuals having been exposed to OPs at a chronic level; 192 R(+) > 192 R(-), respectively.

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