Conjugation of polychlorinated agrochemical sulphoxides and sulphones by glutathione

Dulik, Deanne M.; Huwe, Janice K.; Bakke, J. E.; Connors, M. S.; Fenselau, Catherine

doi:10.3109/00498259209046644

Cited by 7 publications

(5 citation statements)

References 14 publications

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“…Thus, when GSH is present in the incubation samples, the sulfone and sulfoxide metabolite formation were partially or completely consumed as intermediates to the GSH adduct, shunting the metabolism to GSH adduct formation. There have been previous reports on nucleophilic displacement of methylsulfone/sulfonamide by GSH under nonenzymatic and/or enzymatic conditions. ,− …”

Section: Resultsmentioning

confidence: 99%

Bioactivation of 2-(Alkylthio)-1,3,4-Thiadiazoles and 2-(Alkylthio)-1,3-Benzothiazoles

Yang

Qiu

Josephs

et al. 2012

Chem. Res. Toxicol.

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Certain functional groups/structural motifs are known to generate chemically reactive metabolites that can covalently modify essential cellular macromolecules and, therefore, have the potential to disrupt biological function and elicit idiosyncratic adverse drug reactions. In this report, we describe the bioactivation of 5-substituted 2-(alkylthio)-1,3,4-thiadiazoles and 2-(alkylthio)-1,3-benzothiazoles, which can be added to the growing list of structural alerts. When 5-substituted 2-(methylthio)-1,3,4-thiadiazoles and 2-(methylthio)-1,3-benzothiazole were incubated with pooled human liver microsomes in the presence of NADPH and GSH, unusual GSH adducts were formed. Characterization of these GSH adducts by high-resolution mass spectrometry indicated the replacement of the methylthio- group by GSH, and NMR experiments ascertained the proposed structures. On the basis of the metabolic profile change in incubation samples with/without GSH, we proposed that the GSH adduct formation involved two steps: (1) enzymatic oxidation of the alkylthio- group to form sulfoxide and sulfone and (2) nucleophilic displacement of the formed sulfoxide and sulfone by GSH. The proposed mechanism was confirmed by the formation of the same GSH adduct from the incubation of synthetically prepared sulfoxide and sulfone compounds in buffer. We found the sulfur oxidation step was significantly inhibited (80-100%) by preincubation with 1-aminobenzotriazole but was much less affected by thermoinactivation (0-45%), suggesting that the sulfoxidation step is primarily catalyzed by cytochrome P450s and not by flavin monooxygenases. We also investigated the presence of this bioactivation pathway in more than a dozen compounds containing 2-(alkylthio)-1,3,4-thiadiazole and 2-(alkylthio)-1,3-benzothiazoles. The common GSH adduct formation pathway demonstrated by current studies raises a new structural alert and potential liability in drug safety when 2-alkylthio derivatives of 1,3-benzothiazoles and 1,3,4-thiadiazoles are incorporated in drug design.

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Section: Resultsmentioning

confidence: 99%

Bioactivation of 2-(Alkylthio)-1,3,4-Thiadiazoles and 2-(Alkylthio)-1,3-Benzothiazoles

Yang

Qiu

Josephs

et al. 2012

Chem. Res. Toxicol.

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“…In the case of PCPMs, the FAB-MS measurement succeeded in directly identifying their glutathione conjugates. 86) The concomitant formation of S-methyl glutathione with O-demethylation of tetrachlorvinphos was observed by incubation in the hepatic cytosolic fractions with glutathione, showing that GST catalyzes this reaction. 87)…”

Section: In Vitro Metabolismmentioning

confidence: 96%

“…GSTs, the homo or heterodimers with each subunit having a molecular weight of 24-28 kDa, catalyze the reaction of glutathione at the electrophilic site of a pesticide and its metabolites, 83) as reported for the O-demethylation of many OP pesticides. 52,84,85) The intact glutathione conjugate has been detected rarely in the avian metabolism, 86,87) due to the successive metabolism by peptidases and N-acetyltransferases finally to form a mercapturic acid conjugate. 83) When the herbicide propachlor was orally administered to hens, the cysteine and mercapturic acid conjugated via the reaction of glutathione at the chloromethyl carbon were detected as the main metabolites in the excreta.…”

Section: Glutathione S-transferases (Gst)mentioning

confidence: 99%

Acute toxicity and metabolism of pesticides in birds

Katagi

Fujisawa

2021

J. Pestic. Sci.

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The median lethal dose of pesticide in acute oral toxicity, used as a conservative index in avian risk assessment, varies by the species with differences of less than one order of magnitude, depending on body size, feeding habit, and metabolic enzyme activity. The profiles of pesticide metabolism in birds with characteristic conjugations are basically common to those in mammals, but less information is available on their relevant enzymes. The higher toxicity of some pesticides in birds than in mammals is due to the lower activity of avian metabolic enzymes. The bioaccumulation in birds is limited for very hydrophobic pesticides resistant to metabolic degradation. Several in silico approaches using the descriptors of a pesticide molecule have recently been employed to estimate the profiles of acute oral toxicity and bioaccumulation.

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“…This assumption is supported by the data reported in the literature. For example, Dulik et al showed that both pentachlorophenyl methyl sulfoxide and pentachlorophenyl methyl sulfone are the substrates for microsomal and cytosolic glutathione-S-transferase of rabbit, monkey, chicken and human liver [36]. According to Campbell et al, both molinate sulfoxide and sulfone are electrophilic and form glutathione conjugates [28].…”

Section: Conjugation Of Bemethyl and Its Oxidation Products With Glutathione According To Molecular Modeling Datamentioning

confidence: 99%

Investigation of Bemethyl Biotransformation Pathways by Combination of LC–MS/HRMS and In Silico Methods

Belinskaia

Savelieva

Karakashev

et al. 2021

IJMS

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Bemethyl is an actoprotector, an antihypoxant, and a moderate psychostimulant. Even though the therapeutic effectiveness of bemethyl is well documented, there is a gap in knowledge regarding its metabolic products and their quantitative and qualitative characteristics. Since 2018, bemethyl is included to the Monitoring Program of the World Anti-Doping Agency, which highlights the challenge of identifying its urinary metabolites. The objective of the study was to investigate the biotransformation pathways of bemethyl using a combination of liquid chromatography-high-resolution mass spectrometry and in silico studies. Metabolites were analyzed in a 24 h rat urine collected after oral administration of bemethyl at a single dose of 330 mg/kg. The urine samples were prepared for analysis by a procedure developed in the present work and analyzed by high performance liquid chromatography–tandem mass spectrometry. For the first time, nine metabolites of bemethyl with six molecular formulas were identified in rat urine. The most abundant metabolite was a benzimidazole–acetylcysteine conjugate; this biotransformation pathway is associated with the detoxification of xenobiotics. The BioTransformer and GLORY computational tools were used to predict bemethyl metabolites in silico. The molecular docking of bemethyl and its derivatives to the binding site of glutathione S-transferase has revealed the mechanism of bemethyl conjugation with glutathione. The findings will help to understand the pharmacokinetics and pharmacodynamics of actoprotectors and to improve antihypoxant and adaptogenic therapy.

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Conjugation of polychlorinated agrochemical sulphoxides and sulphones by glutathione

Cited by 7 publications

References 14 publications

Bioactivation of 2-(Alkylthio)-1,3,4-Thiadiazoles and 2-(Alkylthio)-1,3-Benzothiazoles

Bioactivation of 2-(Alkylthio)-1,3,4-Thiadiazoles and 2-(Alkylthio)-1,3-Benzothiazoles

Acute toxicity and metabolism of pesticides in birds

Investigation of Bemethyl Biotransformation Pathways by Combination of LC–MS/HRMS and In Silico Methods

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