Lysine- and cysteine-based protein adductions derived from toxic metabolites of 8-epidiosbulbin E acetate

Lin, Dongju; Wang, Kai; Guo, Xiuping; Gao, Huiyuan; Peng, Ying; Zheng, Jiang

doi:10.1016/j.toxlet.2016.10.007

Cited by 24 publications

(33 citation statements)

References 24 publications

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“…The three adducts were all detected in the liver samples of mice given EEA, and their formation was time-and dose-dependent. Pretreatment with BSO increased cysteine-/lysine-based protein adduction and somewhat reduced GSH-/lysine-based protein adduction, indicating GSH depletion made the cysteine residues easier to be attacked by the reactive metabolites formed in the metabolic activation, resulting in hepatotoxicity through protein modification (Lin et al, 2016b).…”

Section: -Epidiosbulbin E Acetatementioning

confidence: 99%

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Metabolic Activation and Hepatotoxicity of Furan-Containing Compounds

2022

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Furan-containing compounds are abundant in nature, of which many but not all have been found to be hepatotoxic and carcinogenic. The furan ring present in the chemical structures may be one of the domineering factors to bring about the toxic response resulting from the generation of reactive epoxide or cis-enedial intermediates which are of the potential to react with biomacromolecules. This review sets out to explore the relationship between the metabolic activation and hepatotoxicity of furan-containing compounds on the strength of scientific reports on several typical alkylated furans, synthetic pharmaceuticals and components extracted from herbal medicines. The pharmacological activities as well as concrete evidence of their liver injuries are described, and the potential toxic mechanisms were discussed partly based on our previous work. Efforts were made to understand the development of liver injury and seek solutions to prevention and interference of the adverse effects.

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Section: -Epidiosbulbin E Acetatementioning

confidence: 99%

“…Scheme 11. Proposed pathways of protein and amino acid adduction resulting from the metabolic activation of EEA (Lin et al, 2016b).…”

Section: Authorship Contributionsmentioning

confidence: 99%

Metabolic Activation and Hepatotoxicity of Furan-Containing Compounds

2022

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“…Animal studies also revealed that oral administration of ethanol extracts of D. bulbifera could cause the significant liver injury, together with increased lipid peroxide levels in liver ( Wang et al, 2010 ). Belonging to clane-type diterpene lactone with furane ring, diosbulbin B, diosbulbin D, and 8-epidiosbulbin E Acetate are principal constituents of D. bulbifera , which were verified to cause obvious liver toxicity towards on rat or mouse, respectively ( Lin et al, 2015 ; Lin et al, 2016a ; Lin et al, 2016b ). Although there is no furan in the structure of pulegone, it can be initially biotransformed to menthofuran after metabolism ( Thomassen et al, 1990 ), and menthofuran can further generate toxic metabolites, after metabolic activation ( Ravindranath et al, 1984 ; Ravindranath et al, 1986 ).…”

Section: Cyp450s Mediated Metabolic Activation Of Natural Products Leading To Toxicitymentioning

confidence: 99%

“…Therefore, the structure-toxicities relationship of furanoterpenoids revealed that unsaturated furan ring moiety is the hepatoxic functional group ( Table 1 ). Meanwhile, CYP450s-mediated epoxidation occurred in the furan of diosbulbin B was regarded as metabolic activation, forming a reactive intermediate of cis-enedial ( Yang et al, 2014 ; Lin et al, 2016a ). The formation of cis-enedial intermediate in liver microsomes ( Lin et al, 2014 ), and CYP3A4-transfected primary rat hepatocytes, HepG2 and L02 cells ( Jiang et al, 2017 ) were significantly inhibited by the potent CYP3A inhibitor of ketoconazole ( Lin et al, 2014 ; Jiang et al, 2017 ).…”

Section: Cyp450s Mediated Metabolic Activation Of Natural Products Leading To Toxicitymentioning

confidence: 99%

Metabolic Activation of the Toxic Natural Products From Herbal and Dietary Supplements Leading to Toxicities

Wang

Xia

et al. 2021

Front. Pharmacol.

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Currently, herbal and dietary supplements have been widely applied to prevent and treat various diseases. However, the potential toxicities and adverse reactions of herbal and dietary supplements have been increasingly reported, and have gradually attracted widespread attention from clinical pharmacists and physicians. Metabolic activation of specific natural products from herbal and dietary supplements is mediated by hepatic cytochrome P450 or intestinal bacteria, and generates chemical reactive/toxic metabolites that bind to cellular reduced glutathione or macromolecules, and form reactive metabolites-glutathione/protein/DNA adducts, and these protein/DNA adducts can result in toxicities. The present review focuses on the relation between metabolic activation and toxicities of natural products, and provides updated, comprehensive and critical comment on the toxic mechanisms of reactive metabolites. The key inductive role of metabolic activation in toxicity is highlighted, and frequently toxic functional groups of toxic natural products were summarized. The biotransformation of drug cytochrome P450 or intestinal bacteria involved in metabolic activation were clarified, the reactive metabolites-protein adducts were selected as biomarkers for predicting toxicity. And finally, further perspectives between metabolic activation and toxicities of natural products from herbal and dietary supplements are discussed, to provide a reference for the reasonable and safe usage of herbal and dietary supplements.

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“…LIM is a furan-containing component. Many xenobiotics containing a furan unit are reported to be toxic and/or carcinogenic [ 12 ], such as furosemide [ 13 ], prazosin [ 14 ], teucrin A [ 15 – 17 ], 8-epidiosbulbin E [ 18 – 20 ], and diosbulbin B [ 21 , 22 ]. The toxic effects elicited by these furans are suggested to be attributed to their cis -enedial oxidative intermediate [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Detection and Structural Characterization of Nucleophiles Trapped Reactive Metabolites of Limonin Using Liquid Chromatography-Mass Spectrometry

Deng

et al. 2018

Journal of Analytical Methods in Chemistry

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Limonin (LIM), a furan-containing limonoid, is one of the most abundant components of Dictamnus dasycarpus Turcz. Recent studies demonstrated that LIM has great potential for inhibiting the activity of drug-metabolizing enzymes. However, the mechanisms of LIM-induced enzyme inactivation processes remain unexplored. The main objective of this study was to identify the reactive metabolites of LIM using liquid chromatography-mass spectrometry. Three nucleophiles, glutathione (GSH), N-acetyl cysteine (NAC), and N-acetyl lysine (NAL), were used to trap the reactive metabolites of LIM in in vitro and in vivo models. Two different types of mass spectrometry, a hybrid quadrupole time-of-flight (Q-TOF) mass spectrometry and a LTQ velos Pro ion trap mass spectrometry, were employed to acquire structural information of nucleophile adducts of LIM. In total, six nucleophile adducts of LIM (M1–M6) with their isomers were identified; among them, M1 was a GSH and NAL conjugate of LIM, M2–M4 were glutathione adducts of LIM, M5 was a NAC and NAL conjugate of LIM, and M6 was a NAC adduct of LIM. Additionally, CYP3A4 was found to be the key enzyme responsible for the bioactivation of limonin. This metabolism study largely facilitates the understanding of mechanisms of limonin-induced enzyme inactivation processes.

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Lysine- and cysteine-based protein adductions derived from toxic metabolites of 8-epidiosbulbin E acetate

Cited by 24 publications

References 24 publications

Metabolic Activation and Hepatotoxicity of Furan-Containing Compounds

Metabolic Activation and Hepatotoxicity of Furan-Containing Compounds

Metabolic Activation of the Toxic Natural Products From Herbal and Dietary Supplements Leading to Toxicities

Detection and Structural Characterization of Nucleophiles Trapped Reactive Metabolites of Limonin Using Liquid Chromatography-Mass Spectrometry

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