<i>In Vitro</i> and <i>In Vivo</i> Metabolic Activation and Hepatotoxicity of Environmental Pollutant 2,6-Dimethylphenol

Zhang, Mingyu; Hu, Yaodong; Li, Wei; Sun, Chen; Guan, Chunjing; Peng, Ying; Zheng, Jiang

doi:10.1021/acs.chemrestox.2c00048

Cited by 4 publications

(4 citation statements)

References 23 publications

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“…Separately, mice were administered IPC at the same dose as above for urine collection, and urine samples were collected. Similar protocols were executed for sample preparation including liver tissues and urine, as described in our publication . All animal experiments were carried out in triplicate.…”

Section: Methodsmentioning

confidence: 99%

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Metabolic Activation of Pesticide Isoprocarb Mediated by CYP3A4 and the Possible Correlation with Its Cytotoxicity

Guan

Zhao

Sun

et al. 2023

J. Agric. Food Chem.

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Isoprocarb (IPC), one of the most important carbamate pesticides, is used to control pests, such as rice planthoppers in crops. Studies have found that IPC induced hepatotoxicity in poultry chicken. However, the mechanisms of IPC-induced hepatotoxicity are unclear. The objectives of this study were to characterize reactive metabolites of IPC in vitro and in vivo, to identify cytochrome P450 enzymes for metabolic activation, and to define a possible correlation between the metabolic activation and cytotoxicity of IPC. In GSH- or NAC-supplemented microsomal incubations, one GSH conjugate (M6) and two NAC conjugates (M7 and M8) were detected after exposure to IPC. The corresponding GSH conjugate and NAC conjugates were found in the liver homogenates and urine of mice after IPC administration. IPC was found to be metabolized to a quinone intermediate reactive to GSH in vitro and in vivo. IPC was found to induce marked cytotoxicity in cultured mouse primary hepatocytes. Ketoconazole, a selective CYP3A4/5 enzyme inhibitor, attenuated the susceptibility of hepatocytes to IPC cytotoxicity.

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Section: Methodsmentioning

confidence: 99%

“…Similar protocols were executed for sample preparation including liver tissues and urine, as described in our publication. 22 All animal experiments were carried out in triplicate.…”

Section: Animal Experimentsmentioning

confidence: 99%

Metabolic Activation of Pesticide Isoprocarb Mediated by CYP3A4 and the Possible Correlation with Its Cytotoxicity

Guan

Zhao

Sun

et al. 2023

J. Agric. Food Chem.

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“…The toxicity mechanism via methide formation of the environmental pollutant 2,6-dimethylphenol was recently reported in more detail. 38 Adducts with glutathione (GSH) were identified, and a single dose of the phenol induced marked elevation of serum liver enzymes in mice.…”

Section: Selected Examples Of Methide and Sulfate Formationmentioning

confidence: 99%

Non-innocuous Consequences of Metabolic Oxidation of Alkyls on Arenes

Claesson¹,

Parkes²

2022

J. Med. Chem.

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Reactive metabolite (RM) formation is widely accepted as playing a pivotal role in causing adverse idiosyncratic drug reactions, with most attention paid to drug-induced liver injury. Mechanisms of RM formation are determined by the drug’s properties in relation to human enzymes transforming the drug. This Perspective focuses on enzymatic oxidation of alkyl groups on aromatics leading to quinone methides and benzylic alcohol sulfates as RMs, a topic that has not received very much attention. Unlike previous overviews, we will include in our Perspective several fulvene-like methides such as 3-methyleneindole. We also speculate that a few older drugs may form non-reported methides of this class. In addition, we report a few guiding DFT calculations of changes in free energy on going from a benzylic alcohol to the corresponding methide. Particularly facile reactions of 2-aminothiazole-5-methanol and 4-aminobenzyl alcohol are noted.

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“…During biochemical transformations mediated by phase I and/or phase II metabolizing enzymes, chemically reactive metabolites may be formed, leading to various toxic effects . Numerous electrophilic species, such as quinones, quinone methides, and carbon cations, are common reactive intermediates. , Among them, iminoquinone methides stand out as recognized electrophilic species . Despite the limited literature on iminoquinone methide production through metabolic pathways, studies indicate trimethoprim’s bioactivation to a reactive iminoquinone methide intermediate, potentially associated with its toxicity .…”

Section: Introductionmentioning

confidence: 99%

CYP3A4-Mediated Metabolic Activation and Cytotoxicity of Chlortoluron

Guo,

Zhang,

et al. 2024

Chem. Res. Toxicol.

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Chlortoluron (CTU) is an herbicide extensively used in agricultural settings for crop cultivation. Its presence in water has been identified as a pollutant detrimental to aquatic species. The objective of the present study was to explore the metabolic activation and hepatotoxicity of CTU. Through human and rat liver microsomal incubations supplemented with CTU, nicotinamide adenine dinucleotide phosphate (NADPH), and either glutathione or N-acetyl cysteine, a benzylic alcohol metabolite (M1) was discerned, alongside a phenol metabolite (M2), a glutathione conjugate (M3), and an N-acetyl cysteine conjugate (M4). In rats exposed to CTU, biliary M3 and urinary M4 were detected in their bile and urine, respectively. The generation of M1 was detected in the presence of NADPH. The observation of M3 and M4 suggests the formation of an iminoquinone methide intermediate arising from the oxidation of M1. CYP3A4 was found to be the principal enzyme catalyzing the metabolic activation of CTU. Furthermore, CTU exhibited cytotoxic properties in cultured rat primary hepatocytes in a concentration-dependent pattern. Concomitant treatment of hepatocytes with ketoconazole mitigated their susceptibility to the cytotoxic effects of CTU.

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In Vitro and In Vivo Metabolic Activation and Hepatotoxicity of Environmental Pollutant 2,6-Dimethylphenol

Cited by 4 publications

References 23 publications

Metabolic Activation of Pesticide Isoprocarb Mediated by CYP3A4 and the Possible Correlation with Its Cytotoxicity

Metabolic Activation of Pesticide Isoprocarb Mediated by CYP3A4 and the Possible Correlation with Its Cytotoxicity

Non-innocuous Consequences of Metabolic Oxidation of Alkyls on Arenes

CYP3A4-Mediated Metabolic Activation and Cytotoxicity of Chlortoluron

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