Chemical Interaction of Protein Cysteine Residues with Reactive Metabolites of Methyleugenol

Feng, Yanhui; Wang, Hui; Wang, Qian; Huang, Wenlin; Peng, Ying; Zheng, Jiang

doi:10.1021/acs.chemrestox.6b00290

Cited by 20 publications

(18 citation statements)

References 27 publications

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“…Metabolic activation is one of the major mechanisms for drug‐induced hepatotoxicity and has been received more and more attention in recent years . Reactive metabolic intermediates generated play a critical role in drug‐induced hepatotoxicity by adduction with liver protein.…”

Section: Discussionmentioning

confidence: 99%

Studies on hepatotoxicity and toxicokinetics of colchicine

Guo

Chen

et al. 2019

J Biochem & Molecular Tox

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Colchicine (COL) is an alkaloid existing in plants of Liliaceous colchicum. It has widely been used in the treatments of many diseases, such as gout, Familial Mediterranean Fever, and tumor. However, the adverse effects of COL are an obstacle to its safe use. The present studies explored the role of metabolic demethylation in the development of COL‐induced hepatotoxicity. We found that inhibition of CYP3A increased the susceptibility of mice to COL hepatotoxicity, and induction of CYP3A decreased the susceptibility of animals to the hepatotoxicity. The toxicokinetic study demonstrated that pretreatment with ketoconazole caused elevated area under the concentration‐time curve of COL. Three demethylation metabolites of COL were found to be less hepatotoxic than the parent compound. It appears that the formation of electrophilic demethylation metabolites was not involved in the development of COL‐induced liver injury.

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Section: Discussionmentioning

confidence: 99%

Studies on hepatotoxicity and toxicokinetics of colchicine

Guo

Chen

et al. 2019

J Biochem & Molecular Tox

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“…There have been some reports using drug–amino acid adducts released from modified proteins to investigate the modification patterns. , Thus, an enzymatic method coupled with LC-MS/MS was developed to quantify protein adducts formed by osimertinib and its metabolites. The enzymatic method used here required no specific conditions of substrates simplified the operation.…”

Section: Discussionmentioning

confidence: 99%

Quantification of Osimertinib and Metabolite–Protein Modification Reveals Its High Potency and Long Duration of Effects on Target Organs

Gong

Zhuo

Chen

et al. 2021

Chem. Res. Toxicol.

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Covalent drugs are newly developed and proved to be successful therapies in past decades. However, the pharmacokinetics (PK) and pharmacodynamic (PD) studies of covalent drugs now ignore the drug and metabolite−protein modification. The low abundance of modified proteins also prevents its investigation. Herein, a simple, selective, and sensitive liquid chromatography-mass spectrometry (LC-MS)/MS quantitative method was established based on the mechanism of a drug and its metabolite−protein adducts using osimertinib as an example.Five metabolites with covalent modification potential were identified. The drug and its metabolite−cysteine adducts released from modified proteins by a mixed hydrolysis method were developed to characterize the level of the modified proteins. This turned the quantitative objects from proteins or peptides to small molecules, which increased the sensitivity and throughput of the quantitative approach. Accumulation of protein adducts formed by osimertinib and its metabolites in target organs was observed in vivo and long-lasting modifications were noted. These results interpreted the long duration of the covalent drugs' effect from the perspective of both parent and the metabolites. In addition, the established method could also be applied in blood testing as noninvasive monitoring. This newly developed approach showed great feasibility for PK and PD studies of covalent drugs.

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“…Synthesis of d 3 -ME was carried out by following the method we published previously. 21 Chemical synthesis of adenosine, guanosine, and cytidine adducts derived from ME was started with bromination of ME and sequential reaction with individual nucleosides. In brief, a mixture of ME (0.19 g, 1.07 mmol) and NBS (0.15 g, 0.85 mmol) dissolved in dichloromethylene (12 mL) was stirred for 3 h at 40 °C.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

In Vitro and In Vivo Evidence for RNA Adduction Resulting from Metabolic Activation of Methyleugenol

Yang

Feng

Zhang

et al. 2020

J. Agric. Food Chem.

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Methyleugenol (ME) is a ubiquitous component in spices and other culinary herbal products. A prevailing theory in ME toxicity is its ability to be metabolically activated by P450 enzymes and sulfotransferases, which initiates sequential reactions of the resulting metabolites with functional biomolecules. The present study aimed at a potential interaction between the reactive metabolites of ME and RNA. Cultured mouse primary hepatocytes were incubated with ME followed by RNA extraction and NaOH and alkaline phosphatase-based RNA hydrolysis. Three adenosine adducts were detected in the hydrolytic mixture by LC−MS/MS. The same adenosine adducts were also detected in hepatic tissues harvested from ME-treated mice. These three adducts were chemically synthesized and structurally characterized by 1 H NMR. Additionally, two guanosine adducts and one cytidine adduct were detected in the in vivo samples. These results provided solid evidence that the reactive metabolites of ME attacked RNA, resulting in RNA adduction.

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Chemical Interaction of Protein Cysteine Residues with Reactive Metabolites of Methyleugenol

Cited by 20 publications

References 27 publications

Studies on hepatotoxicity and toxicokinetics of colchicine

Studies on hepatotoxicity and toxicokinetics of colchicine

Quantification of Osimertinib and Metabolite–Protein Modification Reveals Its High Potency and Long Duration of Effects on Target Organs

In Vitro and In Vivo Evidence for RNA Adduction Resulting from Metabolic Activation of Methyleugenol

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