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The Journal of Toxicological Sciences 2016The oxidative, reductive, and hydrolytic metabolism of methiocarb and the hydrolytic metabolism of carbaryl by liver microsomes and plasma of rats or humans were...
The oxidative, reductive, and hydrolytic metabolism of methiocarb and the hydrolytic metabolism of carbaryl by liver microsomes and plasma of rats or humans were examined. The effects of the metabolism of methiocarb and carbaryl on their nuclear receptor activities were also examined. When methiocarb was incubated with rat liver microsomes in the presence of NADPH, methiocarb sulfoxide, and a novel metabolite, methiocarb sulfone were detected. Methiocarb sulfoxide was oxidized to the sulfone by liver microsomes and reduced back to methiocarb by liver cytosol. Thus, the interconversion between methiocarb and the sulfoxide was found to be a new metabolic pathway for methiocarb by liver microsomes. The product of methiocarb hydrolysis, which is methylthio-3,5-xylenol (MX), was also oxidized to sulfoxide form by rat liver microsomes. The oxidations were catalyzed by human flavin-containing monooxygenase isoform (FMO1). CYP2C19, which is a human cytochrome P450 (CYP) isoform, catalyzed the sulfoxidations of methiocarb and MX, while CYP1A2 also exhibited oxidase activity toward MX. Methiocarb and carbaryl were not enzymatically hydrolyzed by the liver microsomes, but they were mainly hydrolyzed by plasma and albumin to MX and 1-naphthol, respectively. Both methiocarb and carbaryl exhibited PXR and PPARα agonistic activities; however, methiocarb sulfoxide and sulfone showed markedly reduced activities. In fact, when methiocarb was incubated with liver microsomes, the receptor activities were decreased. In contrast, MX and 1-naphthol showed nuclear receptor activities equivalent to those of their parent carbamates. Thus, the hydrolysis of methiocarb and carbaryl and the oxidation of methiocarb markedly modified their nuclear receptor activities.
Topics: Animals; Biotransformation; COS Cells; Carbaryl; Chlorocebus aethiops; Cholinesterase Inhibitors; Constitutive Androstane Receptor; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2C19; Humans; Hydrolysis; Liver; Male; Methiocarb; Microsomes, Liver; Oxidation-Reduction; PPAR alpha; Pregnane X Receptor; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Transfection
PubMed: 27665777
DOI: 10.2131/jts.41.677 -
Drug Metabolism Letters 2018The use of polypharmacy in the present day clinical therapy has made the identification of clinical drug-drug interaction risk an important aspect of drug development... (Comparative Study)
Comparative Study
BACKGROUND
The use of polypharmacy in the present day clinical therapy has made the identification of clinical drug-drug interaction risk an important aspect of drug development process. Although many drugs can be metabolized to sulfoxide and/or sulfone metabolites, seldom is known on the CYP inhibition potential and/or the metabolic fate for such metabolites.
OBJECTIVE
The key objectives were: a) to evaluate the in vitro CYP inhibition potential of selected parent drugs with sulfoxide/sulfone metabolites; b) to assess the in vitro metabolic fate of the same panel of parent drugs and metabolites.
METHODS
In vitro drug-drug interaction potential of test compounds was investigated in two stages; 1) assessment of CYP450 inhibition potential of test compounds using human liver microsomes (HLM); and 2) assessment of test compounds as substrate of Phase I enzymes; including CYP450, FMO, AO and MAO using HLM, recombinant human CYP enzymes (rhCYP), Human Liver Cytosol (HLC) and Human Liver Mitochondrial (HLMit). All samples were analysed by LC-MS-MS method.
RESULTS
CYP1A2 was inhibited by methiocarb, triclabendazole, triclabendazole sulfoxide, and ziprasidone sulfone with IC50 of 0.71 µM, 1.07 µM, 4.19 µM, and 17.14 µM, respectively. CYP2C8 was inhibited by montelukast, montelukast sulfoxide, montelukast sulfone, tribendazole, triclabendazole sulfoxide, and triclabendazole sulfone with IC50 of 0.08 µM, 0.05 µM, 0.02 µM, 3.31 µM, 8.95 µM, and 1.05 µM, respectively. CYP2C9 was inhibited by triclabendazole, triclabendazole sulfoxide, triclabendazole sulfone, montelukast, montelukast sulfoxide and montelukast sulfone with IC50 of 1.17 µM, 1.95 µM, 0.69 µM, 1.34 µM, 3.61 µM and 2.15 µM, respectively. CYP2C19 was inhibited by triclabendazole and triclabendazole sulfoxide with IC50 of 0.25 and 0.22, respectively. CYP3A4 was inhibited by montelukast sulfoxide and triclabendazole with IC50 of 9.33 and 15.11, respectively. Amongst the studied sulfoxide/sulfone substrates, the propensity of involvement of CY2C9 and CYP3A4 enzyme was high (approximately 56% of total) in the metabolic fate experiments.
CONCLUSION
Based on the findings, a proper risk assessment strategy needs to be factored (i.e., perpetrator and/or victim drug) to overcome any imminent risk of potential clinical drug-drug interaction when sulfoxide/sulfone metabolite(s) generating drugs are coadministered in therapy.
Topics: Acetates; Albendazole; Aldicarb; Biotransformation; Cyclopropanes; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Drug Interactions; Humans; Isoenzymes; Methiocarb; Microsomes, Liver; Piperazines; Quinolines; Risk Assessment; Sulfides; Sulfones; Sulfoxides; Thiazoles; Triclabendazole
PubMed: 30117405
DOI: 10.2174/1872312812666180816164626 -
Molecules (Basel, Switzerland) Dec 2020This paper studies the degradation of methiocarb, a highly hazardous pesticide found in waters and wastewaters, through an electro-Fenton process, using a boron-doped...
This paper studies the degradation of methiocarb, a highly hazardous pesticide found in waters and wastewaters, through an electro-Fenton process, using a boron-doped diamond anode and a carbon felt cathode; and evaluates its potential to reduce toxicity towards the model organism . The influence of applied current density and type and concentration of added iron source, Fe(SO)·5HO or FeCl·6HO, is assessed in the degradation experiments of methiocarb aqueous solutions. The experimental results show that electro-Fenton can be successfully used to degrade methiocarb and to reduce its high toxicity towards . Total methiocarb removal is achieved at the applied electric charge of 90 C, and a 450× reduction in the acute toxicity towards , on average, from approximately 900 toxic units to 2 toxic units, is observed at the end of the experiments. No significant differences are found between the two iron sources studied. At the lowest applied anodic current density, 12.5 A m, an increase in iron concentration led to lower methiocarb removal rates, but the opposite is found at the highest applied current densities. The highest organic carbon removal is obtained at the lowest applied current density and added iron concentration.
Topics: Animals; Biodegradation, Environmental; Daphnia; Ecotoxicology; Electrochemistry; Electrodes; Insecticides; Methiocarb; Water Pollutants, Chemical
PubMed: 33322793
DOI: 10.3390/molecules25245893 -
Journal of Food Protection Feb 1995Three carbamate pesticides, aldicarb (A0), ethiofencarb (E0), methiocarb (M0) and six of their oxidized metabolites, sulphoxides (A1, E1, M1) and sulphones (A2, E2, M2)...
Simultaneous Determination of Aldicarb, Ethiofencarb, Methiocarb and Their Oxidized Metabolites in Grains, Fruits and Vegetables by High Performance Liquid Chromatography.
Three carbamate pesticides, aldicarb (A0), ethiofencarb (E0), methiocarb (M0) and six of their oxidized metabolites, sulphoxides (A1, E1, M1) and sulphones (A2, E2, M2) were simultaneously determined. Five grams of a sample were homogenized with acetone, and then treated with dichloromethane-hexane mixture (1:1) and sodium chloride (NaCl), homogenized and centrifuged. The organic layer was removed and the aqueous residue was reextracted a second time with dichloromethane - hexane mixture. The combined organic extracts were evaporated . The residue was dissolved in dichloromethane and charged on a Sep-Pak® aminopropyl cartridge. Carbamates were eluted from the cartridge with 1% methanol in dichloromethane. The eluate was evaporated to dryness and 0.5 ml of methanol and 1.5 ml of 0.001 N-hydrochloric acid (HCl) solution were added. Individual carbamates were separated by gradient elution high performance liquid chromatography (HPLC) using octyldecylsaline (ODS) column. Derivatization of separated carbamates to fluorescent derivatives was achieved in-line. Recovery of pesticides and their oxidized metabolites from rice, apple, cabbage and other foods ranged from 60 to 103% following fortification at 20 ppb. Detection limits were 1 ppb for A1, A2, E1, E2, 2 ppb for A0, E0, M1 and 4 ppb for M0 and M2 (S/N>3).
PubMed: 31121670
DOI: 10.4315/0362-028X-58.2.217 -
Journal of Food Protection Nov 1994Three carbamate pesticides, aldicarb (A0), ethiofencarb (E0), methiocarb (M0) and six of their oxidized metabolites, sulphoxides (A1, E1, M1) and sulphones (A2, E2, M2)...
Simultaneous Determination of Aldicarb, Ethiofencarb, Methiocarb and Their Oxidized Metabolites in Grains, Fruits and Vegetables by High Performance Liquid Chromatography.
Three carbamate pesticides, aldicarb (A0), ethiofencarb (E0), methiocarb (M0) and six of their oxidized metabolites, sulphoxides (A1, E1, M1) and sulphones (A2, E2, M2) were simultaneously determined. Five grams of a sample were homogenized with acetone, and then treated with dichloromethane-hexane mixture (1:1) and sodium chloride (NaCl), homogenized and centrifuged. The organic layer was removed and the aqueous residue was re-extracted a second time with dichloromethane - hexane mixture. The combined organic extracts were evaporated . The residue was dissolved in dichloromethane and charged on a Sep-Pak aminopropyl cartridge. Carbamates were eluted from the cartridge with 1% methanol in dichloromethane. The eluate was evaporated to dryness and 0.5 ml of methanol and 1.5 ml of 0.001 N-hydrochloric acid (HCl) solution were added. Individual carbamates were separated by gradient elution high performance liquid chromatography (HPLC) using octyldecylsaline (ODS) column. Derivatization of separated carbamates to fluorescent derivatives was achieved in-line. Recovery of pesticides and their oxidized metabolites from rice, apple, cabbage and other foods ranged from 60 to 103% following fortification at 20 ppb. Detection limits were 1 ppb for A1, A2, E1, E2, 2 ppb for A0, E0, M1 and 4 ppb for M0 and M2 (S/N>3).
PubMed: 31121722
DOI: 10.4315/0362-028X-57.11.1001 -
Insects Jun 2021Terrestrial gastropod molluscs (slugs and snails) (Mollusca: Gastropoda) cause significant crop damage around the world. There is no formal approach for differentiating... (Review)
Review
Terrestrial gastropod molluscs (slugs and snails) (Mollusca: Gastropoda) cause significant crop damage around the world. There is no formal approach for differentiating between slugs and snails; however, an organism is usually considered a slug when there is no external shell, or when the shell is small in comparison to the body, and a snail when there is a large external shell. Although snails are an important pest of many crops, this review focuses on slug pests and their nonchemical control measures. A recent study by the UK Agriculture and Horticulture Development Board concluded that the failure to control slugs could cost the UK agriculture industry over GBP 100 million annually, with similar figures reported around the world. Whilst slugs are mostly controlled using chemical molluscicide products, some actives have come under scrutiny due to their detrimental environmental effects and impact on nontarget organisms. This has resulted in the ban of actives such as methiocarb in the UK and EU, and, more recently, the ban of metaldehyde in the UK. Therefore, there is an urgent need to find alternative and effective nontoxic solutions in the interest of global food security. In this paper, we have integrated extant literature on the three main biological control agents of slugs, namely nematodes, carabid beetles and sciomyzid flies, and various promising bio-rational slug control strategies. The review also highlights current research gaps and indicates some relevant potential future directions towards developing environmentally benign slug control solutions.
PubMed: 34200919
DOI: 10.3390/insects12060541 -
EFSA Journal. European Food Safety... Oct 2018The conclusions of EFSA following the peer review of the initial risk assessments carried out by the competent authorities of the rapporteur Member State the United... (Review)
Review
The conclusions of EFSA following the peer review of the initial risk assessments carried out by the competent authorities of the rapporteur Member State the United Kingdom and co-rapporteur Member State Germany for the pesticide active substance methiocarb are reported. The context of the peer review was that required by Commission Implementing Regulation (EU) No 844/2012. The conclusions were reached on the basis of the evaluation of the representative use of methiocarb as an insecticide and a bird repellent on maize. The reliable end points, appropriate for use in regulatory risk assessment, are presented. Missing information identified as being required by the regulatory framework is listed. Concerns are identified.
PubMed: 32625712
DOI: 10.2903/j.efsa.2018.5429 -
Frontiers in Veterinary Science 2020Nowadays the intentional poisoning of domestic and wild animals is a crime in the European Union (EU), but as in the past the poison is still used in rural areas of a...
Nowadays the intentional poisoning of domestic and wild animals is a crime in the European Union (EU), but as in the past the poison is still used in rural areas of a number of European countries to kill animals that were considered harmful for human activities. From January 2014 up until October 2020, the Laboratory of Pharmacology and Toxicology of the Faculty of Veterinary Medicine (LFT-FMV) has done the analytical detection of poisoning substances in 503 samples of wildlife and domestic animals and pesticides residues were found in 239 of the samples analyzed. In this retrospective study, toxicology results from domestic species (dog, cat, sheep, cows, and horses), wildlife species (red foxes, birds of prey, lynx, and wild boar), and food baits, are presented. During this period the samples analyzed at the LFT-FMV, were received from all over the country. Analytical detections were performed via solvent extraction followed by thin layer chromatography. Molluscicides (47%, = 109) and Carbamates (24%, = 57) were found to be the first category of pesticides involved in intoxications, in both domestic and wild animals, followed by rodenticides (13%, = 30)-in this group second and third generation, were the most represented; Strychnine is the third (11%, = 26) even though this pesticide has been banned in Portugal since 1988 and in the European Union since 2006 and finally Organophosphates (5%, = 11) in the small number. This study allowed to realize that a great number of positive samples involved banned pesticides (i.e., Aldicarb and Strychnine) but, at the same time, many positives cases were due to the exposure to commercially available products (i.e., Methiocarb and Anticoagulant rodenticides). Also, it's possible to identify the areas where domestic species are the most affected (i.e., Setubal and Lisboa) and the areas where the wild animals are the mainly affected species (i.e., Faro, Castelo Branco, and Bragança).
PubMed: 33521089
DOI: 10.3389/fvets.2020.616293 -
PloS One 2020In bovine mammary glands, the ABCG2 transporter actively secretes xenobiotics into dairy milk. This can have significant implications when cattle are exposed to...
In bovine mammary glands, the ABCG2 transporter actively secretes xenobiotics into dairy milk. This can have significant implications when cattle are exposed to pesticide residues in feed. Recent studies indicate that the fungicide prochloraz activates the aryl hydrocarbon receptor (AhR) pathway, increasing bovine ABCG2 (bABCG2) gene expression and efflux activity. This could enhance the accumulation of bABCG2 substrates in dairy milk, impacting pesticide risk assessment. We therefore investigated whether 13 commonly used pesticides in Europe are inducers of AhR and bABCG2 activity. MDCKII cells expressing mammary bABCG2 were incubated with pesticides for up to 72 h. To reflect an in vivo situation, applied pesticide concentrations corresponded to the maximum residue levels (MRLs) permitted in bovine fat or muscle. AhR activation was ascertained through CYP1A mRNA expression and enzyme activity, measured by qPCR and 7-ethoxyresorufin-Ο-deethylase (EROD) assay, respectively. Pesticide-mediated increase of bABCG2 efflux activity was assessed using the Hoechst 33342 accumulation assay. For all assays, the known AhR-activating pesticide prochloraz served as a positive control, while the non-activating tolclofos-methyl provided the negative control. At 10-fold MRL concentrations, chlorpyrifos-methyl, diflufenican, ioxynil, rimsulfuron, and tebuconazole significantly increased CYP1A1 mRNA levels, CYP1A activity, and bABCG2 efflux activity compared to the vehicle control. In contrast, dimethoate, dimethomorph, glyphosate, iprodione, methiocarb and thiacloprid had no impact on AhR-mediated CYP1A1 mRNA levels, CYP1A activity or bABCG2 efflux. In conclusion, the MDCKII-bABCG2 cell model proved an appropriate tool for identifying AhR- and bABCG2-inducing pesticides. This provides an in vitro approach that could reduce the number of animals required in pesticide approval studies.
Topics: ATP Binding Cassette Transporter, Subfamily G, Member 2; Animal Testing Alternatives; Animals; Cattle; Dogs; Fungicides, Industrial; Germany; Lactation; Madin Darby Canine Kidney Cells; Receptors, Aryl Hydrocarbon; Recombinant Proteins; Toxicity Tests, Chronic
PubMed: 32764792
DOI: 10.1371/journal.pone.0237163 -
International Journal of Environmental... Feb 2022Pesticides are widely applied all over the world, and pesticide exposure can induce different biological effects posing a possible threat to human health. Due to their...
Pesticides are widely applied all over the world, and pesticide exposure can induce different biological effects posing a possible threat to human health. Due to their effects on the endocrine system, some pesticides are classified as endocrine disruptors. The aim of the study is to assess the interference of five pesticides on estrogen biosynthesis and estrogen signaling. Three neonicotinoid insecticides (Acetamiprid, Clothianidin, and Thiamethoxam), a carbamate insecticide (Methiocarb) and a herbicide (Oxadiazon) were tested. The effect of pesticides on estrogen biosynthesis was studied through an ELISA assay using a recombinant form of human aromatase, the enzyme that catalyzes the transformation of androgens to estrogens. Moreover, the effect of pesticides on estrogen signaling was assessed using a gene reporter assay on MELN cells, which measures estrogen receptor-mediated estrogenic activity. The results of the ELISA assay showed that the pesticides did not alter aromatase activity (no interference with estrogen biosynthesis), while the results of the gene reporter assay showed that only Methiocarb was able to alter estrogen signaling at high doses. The estrogenic activity of Methiocarb, expressed as 17β-estradiol equivalency factor (EEF), was equal to 8.0 × 10. In conclusion, this study suggested that Methiocarb should be considered a potential endocrine disruptor.
Topics: Aromatase; Endocrine Disruptors; Estrogens; Humans; Pesticides; Receptors, Estrogen
PubMed: 35206146
DOI: 10.3390/ijerph19041959