Assessing protection against OP pesticides and nerve agents provided by wild-type HuPON1 purified from Trichoplusia ni larvae or induced via adenoviral infection

Hodgins, Sean M.; Kasten, Shane A.; Harrison, Joshua; Otto, Tamara C.; Oliver, Zeke P.; Rezk, Peter; Reeves, Tony E.; Chilukuri, Nageswararao; Cerasoli, Douglas M.

doi:10.1016/j.cbi.2012.10.015

Cited by 18 publications

(8 citation statements)

References 21 publications

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“…Interestingly, in the latter study, the increased PON1 afforded protection of cells against the toxicity of soman and sarin (Curtin et al, 2008). The recent report by Hodgins et al (2013) supports the point that the catalytic efficiency for hydrolysis of a specific OP must be sufficiently high to protect against exposure to that specific OP. However, it also has been argued (Valiyaveettil et al, 2012) that a moderate increase of PON1 (less than twofold) may perhaps be sufficient to provide some protection against some of the symptoms of OP exposures, as shown by the protection seen against sarin and soman in guinea pigs (Valiyaveettil et al, 2011a,b).…”

Section: Pon1 As a Therapeutic Agentmentioning

confidence: 55%

“…Although there was only a modest increase in plasma PON1 activity, PON1 from both species significantly increased survival time and antagonized several effects of the nerve agents, including AChE inhibition in brain. In apparent contrast to these findings, a more detailed study by Hodgins et al (2013) reported that administration of wild-type human PON1 purified from T. ni larvae (Otto et al, 2010) or induced via adenoviral infection in mice protected against the toxicity of the OP insecticides diazoxon and chlorpyrifos oxon, but not of several nerve agents (tabun, soman, sarin, cyclosarin). Protective effects were essentially identical to those of the other study.…”

Section: Pon1 and The Toxicity Of Nerve Agentsmentioning

confidence: 82%

“…PON1 is a human protein, suggesting the possible absence of immunological response. Experiments using mice and guinea pigs have clearly shown that administration of purified human PON1 or of recombinant PON1 protects animals against the toxicity of specific OP compounds, provided that the catalytic efficiency is sufficient Cowan et al, 2001;Stevens et al, 2008;Duysen et al, 2011;Valiyaveettil et al, 2011a,b;Hodgins et al, 2013). Experiments using mice and guinea pigs have clearly shown that administration of purified human PON1 or of recombinant PON1 protects animals against the toxicity of specific OP compounds, provided that the catalytic efficiency is sufficient Cowan et al, 2001;Stevens et al, 2008;Duysen et al, 2011;Valiyaveettil et al, 2011a,b;Hodgins et al, 2013).…”

Section: Pon1 As a Therapeutic Agentmentioning

confidence: 99%

“…However, reports of PON1-induced cytotoxicity in macrophages needs to be further investigated (Mackness and Mackness, 2010). In this regard, novel ways to deliver PON1 are being investigated in addition to administration of purified enzyme or of an adenoviral vector (Cowan et al, 2001;Duysen et al, 2011;Hodgins et al, 2013). In this regard, novel ways to deliver PON1 are being investigated in addition to administration of purified enzyme or of an adenoviral vector (Cowan et al, 2001;Duysen et al, 2011;Hodgins et al, 2013).…”

Section: Pon1 As a Therapeutic Agentmentioning

confidence: 99%

See 3 more Smart Citations

Paraoxonase (PON1) and Detoxication of Nerve Agents

Costa

Cole

Furlong

2015

Handbook of Toxicology of Chemical Warfare Agents

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Section: Pon1 As a Therapeutic Agentmentioning

confidence: 55%

Section: Pon1 and The Toxicity Of Nerve Agentsmentioning

confidence: 82%

Section: Pon1 As a Therapeutic Agentmentioning

confidence: 99%

Section: Pon1 As a Therapeutic Agentmentioning

confidence: 99%

See 2 more Smart Citations

Paraoxonase (PON1) and Detoxication of Nerve Agents

Costa

Cole

Furlong

2015

Handbook of Toxicology of Chemical Warfare Agents

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“…Wild-type PON1 hydrolyzes a range of OP pesticide compounds in vitro, including diazoxon, chlorpyrifos, and paraoxon. Although the enzyme offered in vivo protection against diazoxon and chlorpyrifos, it failed to provide protection against paraoxon (Stevens et al, 2008;Duysen et al, 2011;Hodgins et al, 2013). The failure of wild-type PON1 to offer protection against paraoxon is attributed to insufficient catalytic efficiency, which results in the OP compound escaping the blood stream before PON1 is able to reduce the level of exposure below a lethal dose (Li et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Investigation of Evolved Paraoxonase-1 Variants for Prevention of Organophosphorous Pesticide Compound Intoxication

Mata

Rezk

Sabnekar

et al. 2014

J Pharmacol Exp Ther

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We investigated the ability of the engineered paraoxonase-1 variants G3C9, VII-D11, I-F11, and VII-D2 to afford protection against paraoxon intoxication. Paraoxon is the toxic metabolite of parathion, a common pesticide still in use in many developing countries. An in vitro investigation showed that VII-D11 is the most efficient variant at hydrolyzing paraoxon with a k cat /K m of 2.1 Â 10 6 M 21 min 21 and 1.6 Â 10 6 M 21 min 21 for the enzyme expressed via adenovirus infection of 293A cells and mice, respectively. Compared with the G3C9 parent scaffold, VII-D11 is 15-to 20-fold more efficacious at hydrolyzing paraoxon. Coinciding with these results, mice expressing VII-D11 in their blood survived and showed no symptoms against a cumulative 6.3 Â LD 50 dose of paraoxon, whereas mice expressing G3C9 experienced tremors and only 50% survival. We then determined whether VII-D11 can offer protection against paraoxon when present at substoichiometric concentrations. Mice containing varying concentrations of VII-D11 in their blood (0.2-4.1 mg/ml) were challenged with doses of paraoxon at fixed stoichiometric ratios that constitute up to a 10-fold molar excess of paraoxon to enzyme (1.4-27 Â LD 50 doses) and were assessed for tremors and mortality. Mice were afforded complete asymptomatic protection below a paraoxon-to-enzyme ratio of 8:1, whereas higher ratios produced tremors and/or mortality. VII-D11 in mouse blood coeluted with high-density lipoprotein, suggesting an association between the two entities. Collectively, these results demonstrate that VII-D11 is a promising candidate for development as a prophylactic catalytic bioscavenger against organophosphorous pesticide toxicity.

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Organophosphate-Hydrolyzing Enzymes as First-Line of Defence Against Nerve Agent-Poisoning: Perspectives and the Road Ahead

Iyengar

Pande

2016

Protein J

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Nerve agents (NAs) are extremely neurotoxic synthetic organophosphate (OP) compounds exploited as weapons of mass destruction in terrorist attacks and chemical warfare. Considering the current world scenario, there is a persistent threat of NA-exposure to military personals and civilians. Various prophylactic and post-exposure treatments (such as atropine and oximes) available currently for NA-poisoning are inadequate and unsatisfactory and suffer from severe limitations. Hence, developing safe and effective treatment(s) against NA-poisoning is a critical necessity. With regards to counteracting NA-toxicity, the OP-hydrolyzing enzymes (OPHEs), which can hydrolyze and inactivate a variety of NAs, have emerged as promising candidates for the development of prophylactic therapy against NA-poisoning. However, there are many hurdles to be crossed before these enzymes can be brought to therapeutic use in humans. In this article, we have reviewed the various advancements in the field of development of OPHEs as prophylactic against NA-poisoning. The article majorly focuses on the toxic effects of NAs, various available therapies to counteract NA poisoning, the current status of OPHEs and attempts made to improve the various properties of these enzymes. Further, we have also briefly discussed about the prospective work that is needed to be undertaken for developing these OPHEs into those suitable for use in humans.

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Assessing protection against OP pesticides and nerve agents provided by wild-type HuPON1 purified from Trichoplusia ni larvae or induced via adenoviral infection

Cited by 18 publications

References 21 publications

Paraoxonase (PON1) and Detoxication of Nerve Agents

Paraoxonase (PON1) and Detoxication of Nerve Agents

Investigation of Evolved Paraoxonase-1 Variants for Prevention of Organophosphorous Pesticide Compound Intoxication

Organophosphate-Hydrolyzing Enzymes as First-Line of Defence Against Nerve Agent-Poisoning: Perspectives and the Road Ahead

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