Molecular Mechanism of Action and Selectivity of Sodium Ch annel Blocker Insecticides

Abstract

Sodium channel blocker insecticides (SCBIs) are a relatively new class of insecticides that are represented by two commercially registered compounds, indoxacarb and metaflumizone. SCBIs, like pyrethroids and DDT, target voltage-gated sodium channels (VGSCs) to intoxicate insects. In contrast to pyrethroids, however, SCBIs inhibit VGSCs at a distinct receptor site that overlaps those of therapeutic inhibitors of sodium channels, such as local anesthetics, anticonvulsants and antiarrhythmics. This review will recount the development of the SCBI insecticide class from its roots as chitin synthesis inhibitors, discuss the symptoms of poisoning and evidence supporting inhibition of VGSCs as their mechanism of action, describe the current model for SCBI-induced inhibition of VGSCs, present a model for the receptor for SCBIs on VGSCs, and highlight differences between data collected from mammalian and insect experimental models.

Pesticide toxicity: a mechanistic approach

“…Some of them, such as derivatives of the banned pesticide DDT have been shown to induce neural cell death by apoptosis through the activation of mitogen-activated protein kinases (Shinomiya and Shinomiya, 2003[ 156 ]). Toxicity of DDT and pyrethroids was found to be associated with blocking of voltage-gated sodium channels (VGSCs) in plasmatic membrane of neurons (Silver et al, 2017[ 159 ]). The neurotoxic effect of endosulfan is probably realized via its well-known ability to block neuronal GABAA-gated chloride channels (Kamijima1 and Casida, 2000[ 87 ]).…”

Molecular characterization, expression pattern and metabolic activity of flavin‐dependent monooxygenases in Spodoptera exigua

“…Metaflumizone is a semicarbazone insecticide and belongs to the sodium channel blocker insecticide category. It works by blocking sodium channels of target insects, resulting in paralysis as a result of blocking nerve activity (Silver et al ., ). The three FMO enzymes of S. exigua metabolized metaflumizone to different degrees, and the highest activity was exhibited by SeFMO2.…”

“…Insecticide resistance is generally conferred by an increase in detoxification metabolism and a decrease in target binding affinity in the resistant population (Li et al ., ; Dong et al ., ; Tian et al ., ). Our previous work showed that S. exigua populations collected from Huizhou in 2011 and 2012 had developed resistance (over 60‐fold) to a novel insecticide, metaflumizone (Su & Sun, ), which is a blocker of voltage‐gated sodium channels (Silver et al ., ). Studies on biochemical mechanism revealed that the S. exigua population resistant to metaflumizone had higher cytochrome P450 (P450; 1.4‐fold) and esterase (3.4‐fold) activities than the susceptible strain (Lab‐sus), and the inhibitors of esterase and P450 synergize the toxicity of metaflumizone against the resistant strain (HZ12‐meta).…”

Interactions of Dichlorodiphenyltrichloroethane (DDT) and Dichlorodiphenyldichloroethylene (DDE) With Skeletal Muscle Ryanodine Receptor Type 1

“…DDT exerts its insecticidal activity by binding to voltagegated sodium channels on the axons of neurons in insects to stabilize its open state and to inhibit channel inactivation or deactivation (Coats, 1990;Narahashi, 2000;Silver et al, 2017;Zhorov and Dong, 2017). Toxicity studies demonstrate that high concentrations of DDT are required to mediate neurotoxicity in mammals (Silver et al, 2017), thus its endocrine disrupting properties have been more widely investigated.…”

“…DDT exerts its insecticidal activity by binding to voltagegated sodium channels on the axons of neurons in insects to stabilize its open state and to inhibit channel inactivation or deactivation (Coats, 1990;Narahashi, 2000;Silver et al, 2017;Zhorov and Dong, 2017). Toxicity studies demonstrate that high concentrations of DDT are required to mediate neurotoxicity in mammals (Silver et al, 2017), thus its endocrine disrupting properties have been more widely investigated. The original technical mixture of DDT consisted of a combination of both p,p 0 -DDT (77%) and o,p 0 -DDT (23%) with the latter recognized as the more estrogenic isoform (Baker and Lathe, 2018;Gellert et al, 1972;Kojima et al, 2004).…”