Biotransformation of organophosphorus compounds

Jokanović, Milan

doi:10.1016/s0300-483x(01)00463-2

Cited by 289 publications

(142 citation statements)

References 67 publications

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“…Organophosphates are bioactivated by desulfuration of the phosphorothionate sulfur to produce the oxon, a metabolite that is orders of magnitude more potent in cholinesterase inhibition (Neal & Halpert, 1982;Jokanovic, 2001). FMO-dependent oxidation of the thioether moiety produces the sulfoxide, a pathway that represents detoxication compared to oxon production (Hajjar & Hodgson, 1980Kulkarni & Hodgson, 1984;Osimitz & Kulkarni, 1985;Tynes & Hodgson, 1985b;Kinsler et al, 1988Kinsler et al, , 1990Buronfosse et al, 1995;Hodgson et al, 1998;Usmani et al, 2004).…”

Section: Genetic Polymorphisms Of Flavin-containing Monooxygenasementioning

confidence: 99%

Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism

Krueger

Williams

2005

Pharmacology & Therapeutics

515

444

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Flavin-containing monooxygenase (FMO) oxygenates drugs and xenobiotics containing a "softnucleophile", usually nitrogen or sulfur. FMO, like cytochrome P450 (CYP), is a monooxygenase, utilizing the reducing equivalents of NADPH to reduce 1 atom of molecular oxygen to water, while the other atom is used to oxidize the substrate. FMO and CYP also exhibit similar tissue and cellular location, molecular weight, substrate specificity, and exist as multiple enzymes under developmental control. The human FMO functional gene family is much smaller (5 families each with a single member) than CYP. FMO does not require a reductase to transfer electrons from NADPH and the catalytic cycle of the 2 monooxygenases is strikingly different. Another distinction is the lack of induction of FMOs by xenobiotics.In general, CYP is the major contributor to oxidative xenobiotic metabolism. However, FMO activity may be of significance in a number of cases and should not be overlooked. FMO and CYP have overlapping substrate specificities, but often yield distinct metabolites with potentially significant toxicological/pharmacological consequences.The physiological function(s) of FMO are poorly understood. Three of the 5 expressed human FMO genes, FMO1, FMO2 and FMO3, exhibit genetic polymorphisms. The most studied of these is FMO3 (adult human liver) in which mutant alleles contribute to the disease known as trimethylaminuria. The consequences of these FMO genetic polymorphisms in drug metabolism and human health are areas of research requiring further exploration.

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Section: Genetic Polymorphisms Of Flavin-containing Monooxygenasementioning

confidence: 99%

Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism

Krueger

Williams

2005

Pharmacology & Therapeutics

515

444

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“…SOD neutralizes the highly reactive superoxide radical produced by the cell especially under stress condition. Jokanović (2001) reported that a decrease of 20-30% in GSH levels may affect the antioxidant response and lead to oxidative damage and cellular death. GSH decrease induced by carbaryl has been associated with direct ROS scavenging activity.…”

Section: Discussionmentioning

confidence: 99%

Effect of carbaryl on some biochemical changes in PC12 cells: the protective effect of soy isoflavone genistein, and daidzein, and their mixed solution

Gao

Wang

et al. 2016

CyTA - Journal of Food

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(2016) Effect of carbaryl on some biochemical changes in PC12 cells: the protective effect of soy isoflavone genistein, and daidzein, and their mixed solution, CyTA -Journal of Food, 14:4, 587-593, DOI: 10.1080/19476337.2016 To link to this article: https://doi.org/10. 1080/19476337.2016 We planned to investigate the protective effect of soy isoflavone (SIF) genistein (GEN), and daidzein (DAI), and their mixed solution against carbaryl-induced toxicity in PC12 cells. PC12 cells were exposed to carbaryl, pretreated, co-treatment, or posttreatment with three different SIF solutions for indicated times. Exposure to SIF resulted a better survival and cell morphology which were subjected to carbaryl toxicity. Treatment with SIF was also found to reduce malondialdehyde content, superoxide dismutase inhibitory rate, reactive oxygen species generation, acetylcholine levels in medium, and maintain the integrity of mitochondrial membrane potential. It was also found to increase GSH level. In conclusion, SIF can effectively mitigate adverse effects induced by carbaryl. GEN and DAI have a combined effect that is greater than the effect obtained with each isoflavone alone, although they have different effects against carbaryl-induced damage. SIF enhances metabolism of choline and plays a role as both antioxidant and neuroprotectant.Efecto del carbaril en algunos cambios bioquímicos en células PC12: El efecto protector de las isoflavonas genisteína y daidzeína de la soja, además de su solución mixta RESUMEN Nuestro plan fue investigar el efecto protector de las isoflavonas de la soja (SIF), la genisteína (GEN) y la daidzeína (DAI), además de su solución mixta contra la toxicidad inducida por carbaril en células PC12. Las células PC12 estuvieron expuestas a carbaril, tratadas previamente, tratamiento conjunto o tratadas posteriormente con tres soluciones diferentes de SIF durante los tiempos indicados. La exposición a SIF resultó en una mayor supervivencia y morfología celular, las cuales estuvieron sujetas a la toxicidad del carbaril. También se encontró que el tratamiento con SIF redujo el contenido de MDA, el índice de inhibición de SOD, la generación de ROS, los niveles de acetilcolina a intermedio, además de mantener la integridad del potencial de membrana mitocondrial. También se encontró que hizo aumentar el nivel de GSH. En conclusión, SIF puede mitigar de forma eficiente los efectos adversos inducidos por el carbaril. GEN y DAI tienen un efecto combinado que es mayor que el efecto obtenido con cada isoflavona por separado, aunque tienen efectos distintos contra el daño inducido por carbaril. SIF mejora el metabolismo de la colina, además de jugar un papel importante como antioxidante y neuroprotector.

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“…Most OPCs (except phosphates and phosphonates) show no or little anticholinesterase activity in their nonmetabolized form. 83 The biotransformation of non-toxic OPCs to active metabolites occurs through many different reactions, being the most representative of them the oxidative desulfuration of the thiophosphate group, converting the thiophosphoryl bond to a phosphoryl. In this way, phosphorothioates and phosphorodithioates, which are usually weak AChE inhibitors (due to the low electronegativity of sulfur when compared to oxygen), are converted to their oxidized forms, which are extremely toxic anticholinesterase compounds.…”

Section: Organophosphorus Compoundsmentioning

confidence: 99%

“…In this way, phosphorothioates and phosphorodithioates, which are usually weak AChE inhibitors (due to the low electronegativity of sulfur when compared to oxygen), are converted to their oxidized forms, which are extremely toxic anticholinesterase compounds. [83][84][85] Other important metabolic reactions are those that result in the detoxification of OPCs. These processes involve the breaking one of the phosphorus bonds, forming a negatively charged molecule, 83 or the increase in water solubility of the OPC, making its excretion easier and reducing its half-life in the organism.…”

Section: Organophosphorus Compoundsmentioning

confidence: 99%

“…[83][84][85] Other important metabolic reactions are those that result in the detoxification of OPCs. These processes involve the breaking one of the phosphorus bonds, forming a negatively charged molecule, 83 or the increase in water solubility of the OPC, making its excretion easier and reducing its half-life in the organism. 85 …”

Section: Organophosphorus Compoundsmentioning

confidence: 99%

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Organophosphorus compounds as chemical warfare agents: a review

Delfino¹,

Ribeiro²,

Figueroa‐Villar³

2009

J. Braz. Chem. Soc.

231

178

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Os agentes de guerra química constituem uma das maiores ameaças do mundo moderno. Dentre estes, destacam-se os agentes neurotóxicos, em virtude de sua alta letalidade e periculosidade. Eles são compostos organofosforados que atuam pela inibição da enzima acetilcolinesterase, a qual é fundamental no processo de transmissão de impulsos nervosos. Existem várias formas de tratamento para a intoxicação por organofosforados, mas nenhuma delas é eficaz contra todos os agentes conhecidos ou contra todos os seus efeitos. Esta revisão tem como foco o uso de compostos organofosforados como agentes neurotóxicos de guerra química. Após uma breve introdução histórica, será feita uma discussão sobre as principais características estruturais e biológicas da acetilcolinesterase, seguida por uma revisão das propriedades dos compostos organofosforados e da sua aplicação como agentes de guerra química. Por fim, serão discutidas as formas de tratamento contra estes agentes, com ênfase nas oximas usadas para reativar a acetilcolinesterase inibida.Chemical warfare agents constitute one of the greatest threats in the modern world. Among them, the neurotoxic agents are of special interest due to their high lethality and danger. Neurotoxic agents are organophosphorus compounds that act by inhibiting the enzyme acetylcholinesterase, which is fundamental for the control of transmission of nervous impulses. There are several ways of treating intoxication by organophosphorus compounds, but none of them is efficient against all the known neurotoxic agents or against all of their effects. This review focus on the use of organophosphorus compounds as neurotoxic chemical warfare agents. After a brief historical introduction, it will be done a discussion about the structural and biological characteristics of acetylcholinesterase, followed by a review of the properties of organophosphorus compounds and their application as chemical warfare agents. Finally, the ways of treatment against intoxication with these agents will be discussed, with emphasis on the oximes used for reactivating the inhibited acetylcholinesterase.

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Biotransformation of organophosphorus compounds

Cited by 289 publications

References 67 publications

Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism

Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism

Effect of carbaryl on some biochemical changes in PC12 cells: the protective effect of soy isoflavone genistein, and daidzein, and their mixed solution

Organophosphorus compounds as chemical warfare agents: a review

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