New inhibitors of Complex I of the mitochondrial electron transport chain with activity as pesticides (original) (raw)
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Toxicity and mode of action of benzhydrolpiperidines and related compounds in insects
Pesticide Biochemistry and Physiology, 2002
The benzyhydrolpiperidines are a new chemical class of insecticide with potent effects on lepidopteran larvae, but little activity against flies or cockroaches. These materials have a slow action in diet assays, causing progressive mortality over a 10 day period. Signs of intoxication also develop slowly after topical application to Helicoverpa virescens larvae, and include ataxia, paralysis, and curling, with tremors and convulsions occurring when the insects are disturbed. The central nervous system shows depressed nerve activity in prostrate larvae, unlike the hyperexcitation caused by DDT. Similarly, nerve discharge in stretch receptor preparations of tobacco budworm larvae is blocked by benzyhydrolpiperidines, whereas motor nerve activity is apparently unaffected. In cricket synaptosomes, benzyhydrolpiperidines block veratridine-evoked release of labeled acetylcholine, likely by an action on sodium channels, with several compounds having IC 50 values in the nanomolar range. Highest potency was observed for N-oxide compounds, although they required prolonged incubation to observe an effect. Metabolism studies of 14 Clabeled N-oxide observed no conversion consistent with bioactivation to the corresponding piperidine, confirming that the N-oxides possessed intrinsic activity. Overall, the potency for blocking veratridineevoked release in cricket synaptosomes displayed some correlation with LC 50 values for dietary exposure to tobacco budworm larvae, although the most active compound was not toxic to crickets. Thus, a slowly developing sodium channel blockade appears to underlie the mode of action of these compounds, but the effect is only toxicologically significant in susceptible species. Ó 2002 Elsevier Science (USA). All rights reserved.
Recent insights into sublethal effects of pesticides on insect respiratory physiology
Open Access Insect Physiology, 2015
Determination of the sublethal effects of pesticides on insects is a challenging topic because of the vast number of different possible end points. Sublethal effects can manifest themselves through changes in motor activity, behavior, or, in the case of social insects, learning ability. These are still the outcomes of physiological changes. As autonomic processes like respiration assure the normal functioning of any organism, the estimation of disturbances of these processes can give valuable data for toxicology researchers. This review reports a variety of effects of pesticides on insect respiratory patterns, metabolic rate, and water loss rate. Although the tested pesticides and target subjects belong to very different groups, the results of the reviewed studies indicate several common effects. We conclude that the study of the pesticide effects on insect respiratory physiology has potential for further development as a methodology for measurement of basic physiological changes as it allows measurement of the intact living insect, the result is obtained rapidly, and several parameters can be measured simultaneously. At the same time, the method has its shortcomings: the equipment is expensive and complicated, the results can be affected by the experimental conditions, and as yet there are no standardized end points for data comparison.
A novel oxadiazine insecticide is bioactivated in lepidopteran larvae
Archives of Insect Biochemistry and Physiology, 1998
DPX-JW062 is a new insecticide showing strong field activity, especially on Lepidoptera. Metabolism studies in several lepidopteran larvae show that orally administered [ 14 C]DPX-JW062 is rapidly cleaved to a decarbomethoxyllated metabolite (DCJW), based upon HPLC and mass spectrometry identification. The metabolic conversion is correlated with appearance of neurotoxic symptoms. Tissue localization studies with fifth instar Manduca sexta larvae have shown that the fat body and especially midgut are the most active tissues in catalyzing the conversion. The enzyme(s) appears to be localized in many subcellular fractions and can be inhibited by the esterase inhibitors DFP, paraoxon, and DEF but not by the cytochrome p450-dependent monooxygenase inhibitors piperonyl butoxide and 1-phenyl imidazole, or the glutathione S-transferase inhibitor N-ethyl maleimide. The enzyme thus appears to have properties like an esterase/amidase. DCJW is a highly potent blocker of sodium channels in a Manduca sexta larval motor nerve preparation in vitro. The block of compound action potentials in this preparation is voltage-dependent, which is similar to the local anesthetic-like action previously ascribed to dihydropyrazole insecticides. In contrast, DPX-JW062 is weakly active in these blocking actions. We also observe a diminution of spontaneous CNS action potentials which is correlated with neurotoxic symptoms in DPX-JW062-treated larvae. This mode of action is entirely distinct from pyrethroids, which cause prolonged membrane depolarization leading to repetitive nerve firing. In summary, DPX-JW062 appears to be rapidly bioactivated by target insects to the potent insecticidally active sodium channel blocker, the S-enantiomer of its decarbomethoxyllated metabolite. Arch. Insect Biochem. Physiol. 37:91-103, 1998.
Toxicity of Four Dibenzoylhydrazine Correlates with Evagination-Induction in the Cotton Leafworm
Pesticide Biochemistry and Physiology, 2000
Treatment of last-instars of the cotton leafworm, Spodoptera littoralis, with four dibenzoylhydrazines, RH-5849, tebufenozide (RH-5992), halofenozide (RH-0345), and methoxyfenozide (RH-2485), revealed premature molting leading to death. Methoxyfenozide was the most toxic, followed by tebufenozide, halofenozide, and RH-5849. The potency of the four ecdysone agonists to induce evagination in cultured imaginal discs excised from last-instars was measured and compared with the natural insect molting hormone, 20hydroxyecdysone (20E). In parallel, competition percentages for binding were analyzed with whole imaginal wing discs cultured with 3 H-labeled ponasterone A and different concentrations of ecdysone agonist. We found that the four compounds tested caused the effect as agonists of 20E in vitro. The order of toxicity of the four ecdysone agonists corresponded with that for evagination-induction and binding competition with whole imaginal discs.
Bioactivation and mode of action of the oxadiazine indoxacarb in insects
Crop Protection, 2000
DPX-MP062 (indoxacarb) is a novel oxadiazine insecticide which has good "eld activity against a number of pest Lepidoptera, as well as certain Homoptera and Coleoptera. Indoxacarb (discovered and developed by E.I. DuPont and Co.) is a 75%S : 25%R mixture of enantiomers at the chiral bicyclic carbon; DPX-JW062 is the corresponding racemic compound. Several species of lepidopteran larvae can rapidly metabolize C-JW062 to C-DCJW (for N-decarbomethoxyllated JW062) after ingestion, and more slowly after topical treatment; this conversion is correlated with the appearance of neurotoxic symptoms. Several sucking insects are also capable of absorbing and bioactivating indoxacarb after either dermal or oral administration, but do so much more slowly than the Lepidoptera. DCJW is a highly potent, voltage-dependent blocker of Na>-dependent compound action potentials when tested in a Manduca sexta larval abdominal motoneuron preparation; DPX-JW062 was much less potent in this regard. When larvae were poisoned in vivo, onset of paralysis and block of central nervous system action potentials was more rapid with DCJW than with DPX-JW062; onset of neurotoxic symptoms leads to a rapid and irreversible halt in feeding. The S-enantiomer of DCJW is active both in the motoneuron preparation in vitro and in lepidopteran larvae in vivo; however S-DPX-JW062 is active in vivo only, while the R-enantiomers of DCJW and DPX-MP062 are inactive in both. Thus, activation of the parent oxadiazines to the S-enantiomers of the N-decarbomethoxyllated metabolites, which are powerful sodium channel blockers, is the toxic mechanism of action in Lepidoptera and apparently for other pest insects as well; however, the rate of bioactivation is a critical factor in determining the speed and ultimate toxicity of this compound in di!erent insect species. Indoxacarb's inherent activity against Lepidoptera is comparable to the most potent insecticides ever commercialized.
Journal of Plant Protection Research, 2014
It is necessary to study the biochemical changes in insects exposed to toxicants if we want to predict the potential of various chemicals on the natural enemy. Physiological energy, as a biochemical biomarker, may be affected by many pesticides including organophosphate compounds. Therefore, in this study, the sublethal effects of diazinon, fenitrothion, and chlorpyrifos on the cellular energy allocation (CEA) of the predatory bug, Andrallus spinidens Fabricius (Hemiptera: Pentatomidae), a potential biological control agent, was studied on 5th-instar nymphs. Among the energy reserves of the A. spinidens nymphs, only total protein was significantly affected by pesticide treatments, and the highest value was observed in chlorpyrifos treatment. The energy available (Ea) and energy consumption (Ec) in A. spinidens were significantly affected by these pesticides. In exposed bugs, these parameters were affected by fenitrothion and chlorpyrifos more than diazinon. The activity of the elect...
Insect Tolerance to A Neurotoxic Polypeptide: Pharmacokinetic and Pharmacodynamic Aspects
The Journal of Experimental Biology, 1997
AaIT is a single-chain neurotoxic polypeptide (Mr 8×10 3) representative of the excitatory insect-selective neurotoxins derived from Buthinae scorpion venoms (Zlotkin, 1991). The toxin exclusively affects insects, modifying their neuronal Na + conductance by binding to voltage-dependent Na + channels (Gordon et al. 1992). Its strict selectivity for insects, demonstrated by toxicity, by electrophysiology and by binding assays (Zlotkin, 1991), has strongly encouraged its use in pestcontrol technology. This approach, motivated by the public health and environmental hazards that result from the massive utilization of industrial insecticides, led to the genetic combination of a baculovirus and the gene encoding the AaIT toxin. The resulting recombinant baculoviruses, when compared with the wild-type viruses, significantly enhance the lethality to insect pests, thus reducing their feeding damage (Stewart et al. 1991; McCutchen et al. 1991). Furthermore, the AaIT-expressing recombinant baculovirus has recently reached the stage of field trials, providing encouragement for the further employment of insecticidal polypeptide neurotoxins in the design and employment of selective bioinsecticides (Cory et al. 1994). With this background, and because of its neuropharmacological and applicative significance, the basis for differences in toxicity of AaIT between species deserves clarification. This may reveal structural differences in ion channels between insect species and lead to inferred chemical modifications of the clonable neurotoxins. The present study reveals that insect tolerance to AaIT, in addition to the common phenomena of degradation and elimination, also occurs at the pharmacodynamic level in the nature of the interaction of the toxin with its neuronal receptor. Materials and methods Materials Crude venom from the scorpion Androctonus australis was purchased from Latoxan (Rosans, France). The A. australis insect toxin (AaIT) was purified by column chromatography according to a previously described method (Zlotkin et al. 1971b). Inulin [ 14 C]carboxylic acid, for the determination of hemolymph volume and Na[ 125 I] for toxin radioiodination were purchased from Amersham International plc (England).
Neuroscience Letters
Imidacloprid is an insecticide which has the nicotinic acetylcholine receptors (nAChRs) as its primary site of action; acetylcholine is the major excitatory neurotransmitter in the insect central nervous system (CNS). In this study, the action of imidacloprid was tested using the synapses of the respiratory central pattern generator of the beetle Tenebrio molitor. The no observed effect concentration (NOEC) for imidacloprid was estimated to be between 0.001 and 0.010 microM. A concentration of 0.10 microM caused hyperexcitation in firing of the respiratory motoneurons, while the concentration of 1.00 microM caused an abrupt increase in their frequency and then a complete inhibition of the activity of the respiratory motoneurons. The possible implication of the action of such low concentrations of imidacloprid in the contraction of the respiratory muscles is also demonstrated and discussed.
Enzymatic detoxification strategies for neurotoxic insecticides in adults of three tortricid pests
Bulletin of Entomological Research, 2019
We examined the role of the most important metabolic enzyme families in the detoxification of neurotoxic insecticides on adult males and females from susceptible populations of Cydia pomonella (L.), Grapholita molesta (Busck), and Lobesia botrana (Denis & Schiffermüller). The interaction between the enzyme families – carboxylesterases (EST), glutathione-S-transferases (GST), and polysubstrate monooxygenases (PSMO) – with the insecticides – chlorpyrifos, λ-cyhalothrin, and thiacloprid – was studied. Insect mortality arising from the insecticides, with the application of enzyme inhibitors – S,S,S-tributyl phosphorotrithioate (DEF), diethyl maleate (DEM), and piperonyl butoxide (PBO) – was first determined. The inhibitors' influence on EST, GST, and PSMO activity was quantified. EST and PSMO (the phase-I enzymatic activities) were involved in the insecticide detoxification in the three species for both sexes, highlighting the role of EST, whereas GST (phase-II enzymes) was involved...