Carbon-14 balance and residues of dichlorvos and its metabolities in pigs dosed with carbon-14-labeled dichlorvos

Potter, John C.; Loeffler, Josef E.; Collins, R. Douglas; Young, Robert B.; Page, A. C.

doi:10.1021/jf60186a047

Cited by 13 publications

(14 citation statements)

References 7 publications

(7 reference statements)

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“…Although there is abundant evidence that DDVP exposure results in oxidative stress [ 3 ], the underlying mechanism has not been well elucidated. DDVP is metabolized by both glutathione-dependent and glutathione-independent pathways [ 15 – 17 ]. Consistent with our observations at the message level, the activities of a number of enzymes involved in glutathione synthesis and recycling (glutathione reductase, glutathione- S -transferase, glutamate:cysteine ligase) are known to be increased concomitant with an increase in glutathione content in the liver of DDVP exposed fish [ 49 ].…”

Section: Resultsmentioning

confidence: 99%

“…DDVP exposure also reduced the transcript abundance of key enzymes involved in glyoxal detoxification, alanine-glyoxylate aminotransferase ( agxtl ), aldo-keto reductase family 1, member A1 ( akr1a1a ) [ 81 ], and glyoxalase ( glo1 ) (not shown). Glyoxal has been suggested to be a toxic metabolite of DDVP [ 15 – 17 , 82 ] and has the potential on its own to induce cell damage, deplete GSH, generate ROS, collapse the mitochondrial membrane potential, induce lipid peroxidation, and produce formaldehyde[ 4 , 15 – 17 , 25 , 42 , 83 ]. Although direct evidence of glyoxal and its metabolites in tissues exposed to DDVP remains elusive [ 16 ], it is conceivable that glyoxal or its metabolites could exacerbate DDVP toxicity.…”

Section: Resultsmentioning

confidence: 99%

“…DDVP can be detoxified via a glutathione-dependent pathway and can also produce glyoxal which can deplete glutathione [ 15 – 17 ]. DDVP exposure has been associated with diminished glutathione levels in the mitochondria [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

“…The liver is a primary site of DDVP metabolism [ 14 ], where it is converted to desmethyl-dichlorvos, dimethyl phosphate, and dichloroacetaldehyde by glutathione-dependent and aryl esterase pathways [ 4 , 15 – 17 ]. While the metabolism of DDVP was initially described decades ago [ 16 ], the cause of its toxicity in non-neural target organs such as the liver or kidney remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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Dichlorvos exposure results in large scale disruption of energy metabolism in the liver of the zebrafish, Danio rerio

et al. 2015

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BackgroundExposure to dichlorvos (DDVP), an organophosphorus pesticide, is known to result in neurotoxicity as well as other metabolic perturbations. However, the molecular causes of DDVP toxicity are poorly understood, especially in cells other than neurons and muscle cells. To obtain a better understanding of the process of non-neuronal DDVP toxicity, we exposed zebrafish to different concentrations of DDVP, and investigated the resulting changes in liver histology and gene transcription.ResultsFunctional enrichment analysis of genes affected by DDVP exposure identified a number of processes involved in energy utilization and stress response in the liver. The abundance of transcripts for proteins involved in glucose metabolism was profoundly affected, suggesting that carbon flux might be diverted toward the pentose phosphate pathway to compensate for an elevated demand for energy and reducing equivalents for detoxification. Strikingly, many transcripts for molecules involved in β-oxidation and fatty acid synthesis were down-regulated. We found increases in message levels for molecules involved in reactive oxygen species responses as well as ubiquitination, proteasomal degradation, and autophagy.To ensure that the effects of DDVP on energy metabolism were not simply a consequence of poor feeding because of neuromuscular impairment, we fasted fish for 29 or 50 h and analyzed liver gene expression in them. The patterns of gene expression for energy metabolism in fasted and DDVP-exposed fish were markedly different.ConclusionWe observed coordinated changes in the expression of a large number of genes involved in energy metabolism and responses to oxidative stress. These results argue that an appreciable part of the effect of DDVP is on energy metabolism and is regulated at the message level. Although we observed some evidence of neuromuscular impairment in exposed fish that may have resulted in reduced feeding, the alterations in gene expression in exposed fish cannot readily be explained by nutrient deprivation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1941-2) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dichlorvos exposure results in large scale disruption of energy metabolism in the liver of the zebrafish, Danio rerio

et al. 2015

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“…DDVP is well known for its effects on the parasympathetic autonomic nervous system and the neuromuscular systems . Recent studies also suggest that DDVP affects non-neuronal targets in human plasma, the liver, − the kidney, and the reproductive system. , In the liver, the primary site of DDVP metabolism, − DDVP has been shown to induce hepatocellular vacuoles and cell swelling…”

Section: Introductionmentioning

confidence: 99%

Detection of Dichlorvos Adducts in a Hepatocyte Cell Line

et al. 2014

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The toxicity of dichlorvos (DDVP), an organophosphate (OP) pesticide, classically results from modification of the serine in the active sites of cholinesterases. However, DDVP also forms adducts on unrelated targets such as transferrin and albumin, suggesting that DDVP could cause perturbations in cellular processes by modifying noncholinesterase targets. Here we identify novel DDVP-modified targets in lysed human hepatocyte-like cells (HepaRG) using a direct liquid chromatography-mass spectrometry (LC-MS) assay of cell lysates incubated with DDVP or using a competitive pull-down experiments with a biotin-linked organophosphorus compound (10-fluoroethoxyphosphinyl-N-biotinamidopentyldecanamide; FP-biotin), which competes with DDVP for similar binding sites. We show that DDVP forms adducts to several proteins important for the cellular metabolic pathways and differentiation, including glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and actin. We validated the results using purified proteins and enzymatic assays. The study not only identified novel DDVP-modified targets but also suggested that the modification directly inhibits the enzymes. The current approach provides information for future hypothesis-based studies to understand the underlying mechanism of toxicity of DDVP in non-neuronal tissues. The MS data have been deposited to the ProteomeXchange with identifier PXD001107.

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Metrifonate

et al. 1978

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The organophosphorus compound 0,0-dimethyl-(1-hydroxy-2,2,2-trichloroethyl)-phosphonate was introduced as an insecticide, trichlorfon, in 1952 (Lorenz et al., 1955) and as a drug, metrifonate, in the treatment of schistosomiasis in 1960 (Lebrun and Cerf, 1960). This organophosphorus compound is unique in that it has been claimed not to be a direct acting cholinesterase inhibitor but being transformed nonenzymatically into an active component dichlorvos, 2, 2-dichlorovinyl dimethyl phosphate (DDVP). The evidence for this transformation has mostly been indirect. Recently it has been proved chemically and quantitatively that this transformation occurs in the animal body (Nordgren et al., 1978). Metrifonate is the sole organophosphorus compound currently studied clinically in schistosomiasis. A substantial therapeutic effect is obtained only in Schistosoma haematobium infections. In this review on available data of metrifonate it is suggested that further more detailed studies of both S. haematobium and S. mansoni are necessary. This should include studies of the enzymic properties of the worms and the reaction of their esterases towards both metrifonate and DDVP as well as the pharmacokinetics of these compounds in man. In addition there are still unsolved discrepancies reported regarding organ toxicity of the compound which may, however, be due to different grades of parity of the test material.

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Carbon-14 balance and residues of dichlorvos and its metabolities in pigs dosed with carbon-14-labeled dichlorvos

Cited by 13 publications

References 7 publications

Dichlorvos exposure results in large scale disruption of energy metabolism in the liver of the zebrafish, Danio rerio

Dichlorvos exposure results in large scale disruption of energy metabolism in the liver of the zebrafish, Danio rerio

Detection of Dichlorvos Adducts in a Hepatocyte Cell Line

Metrifonate

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