Characterization of emodin metabolites in Raji cells by LC–APCI-MS/MS

Koyama, Junko; Takeuchi, Atsuko; Morita, Izumi; Nishino, Yu; Shimizu, Masaru; Inoue, Munetaka; Kobayashi, N.

doi:10.1016/j.bmc.2009.09.024

Cited by 13 publications

(6 citation statements)

References 42 publications

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“…Cytochromes P450s (CYPs) are the major drug-metabolizing enzymes highly expressed in liver, which catalyze phase I metabolism reactions. It is generally recognized that reactive metabolites formed by phase I metabolizing enzymes have chemical reactivity to endogenous proteins, thereby causing toxic effects. − Phase I metabolism studies demonstrated that emodin was extensively biotransformed into several hydroxylation metabolites including 2-, 4-, 5-, and 7-hydroxyemodin, ω-hydroxyemodin, as well as emodic acid. , Human liver microsome and recombinant CYPs incubation assays indicated the importance of CYP3A4 or other CYPs in emodin biotransformation in phase I metabolism. , CYP3A4, a predominant isoform of CYPs, metabolizes more than 60% of the clinically commonly used drugs . In many cases, CYP3A4 mediates the formation of reactive metabolites of many drugs, and therefore, results in hepatotoxicity. − Currently, however, the relationship between the biotransformation by CYP3A4 and the development of emodin-induced liver injury is not fully disclosed.…”

Section: Introductionmentioning

confidence: 99%

“…9−11 Phase I metabolism studies demonstrated that emodin was extensively biotransformed into several hydroxylation metabolites including 2-, 4-, 5-, and 7-hydroxyemodin, ω-hydroxyemodin, as well as emodic acid. 12,13 Human liver microsome and recombinant CYPs incubation assays indicated the importance of CYP3A4 or other CYPs in emodin biotransformation in phase I metabolism. 14,15 CYP3A4, a predominant isoform of CYPs, metabolizes more than 60% of the clinically commonly used drugs.…”

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confidence: 99%

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CYP3A Activation and Glutathione Depletion Aggravate Emodin-Induced Liver Injury

Jiang

Dong-sheng

et al. 2018

Chem. Res. Toxicol.

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1,3,8-Trihydroxy-6-methylanthraquinone (emodin), a widely existing natural product in herbal medicines, has been reported to be hepatotoxic, but the exact underlying mechanism is still not fully understood. The objective of the present study was to evaluate the role of CYP3A and glutathione (GSH) in emodin-induced liver injury. Primary human hepatocytes were exposed to emodin with and without addition of CYP3A inducer/inhibitor and GSH synthesis inhibitor. It was found that emodin-mediated cytotoxicity increased when CYP3A was activated and GSH was depleted. Hepatotoxicity induced by emodin in rats by activation/inhibition of CYP3A and depletion of GSH was further investigated. Administration of emodin in combination with l-buthionine sulfoximine (BSO) or dexamethasone (DEX) resulted in aggravated liver injury, whereas pretreatment with ketoconazole (KTZ) suppressed the side effects caused by emodin. In addition, plasma exposure of emodin and its glucuronide metabolite were measured by ultraperformance liquid chromatography triple quadrupole mass spectrometry. Emodin and its glucuronide were lower in BSO-, DEX-, and KTZ- co-treated rats compared with those administered with emodin alone. In conclusion, these mentioned results suggested that CYP3A induction and GSH depletion might be involved in hepatotoxicity induced by emodin. This study may help to understand the risk factors and the mechanism of hepatotoxicity of emodin in humans.

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

CYP3A Activation and Glutathione Depletion Aggravate Emodin-Induced Liver Injury

Jiang

Dong-sheng

et al. 2018

Chem. Res. Toxicol.

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“…Emodin (EM, Scheme ) is the major one among the anthraquinone compounds. EM has been found to elicit antipyretic and anti-inflammatory properties. , Both extracts of polygonum multiflorum and purified EM showed inhibitory effects on receptor tyrosine kinase activity and tumor cell growth, along with antibiotic, antiviral, and cytostatic activities . Despite this, numbers of hepatic toxicity cases associated with polygonum multiflorum have been documented. − Additionally, EM was a primary component reportedly responsible for polygonum multiflorum induced hepatotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Chemical Reactivity of Emodin and Its Oxidative Metabolites to Thiols

Qin¹,

Xu²,

Chen³

et al. 2016

Chem. Res. Toxicol.

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Polygonum multiflorum is an herbal medicine widely employed in China. Hepatotoxicity of the herbal medicine has been well documented, but the mechanisms of the toxicity remain unknown. Emodin (EM) is a major constituent of the herb and has been reported to be hepatotoxic. The main purpose of this study was to define the metabolic pathways of EM in order to characterize the potential reactive intermediates. EM was incubated with rat liver microsomes or human liver microsomes, followed by LC-MS/MS analysis to investigate the in vitro and in vivo metabolism of EM. As a result, three monohydroxylation metabolites (M1-M3) were detected after exposure to EM: ω-hydroxyemodin, 2-hydroxyemodin, and 5-hydroxyemodin. Urinary M1 and M2 were detected in rats administered EM. Three mercapturic acids (M4-M6) were found in microsomal incubations containing EM, NADPH, and N-acetylcysteine. It appears that M4 originated from parent compound EM, and M5 and M6 originated from M1 and M2, respectively. Two biliary EM-derived GSH conjugates were found in EM-treated rats. One arose from direct adduction of EM with GSH, and the other was derived from M1. Cytochrome P450's 1A2, 2C19, and 3A4 were the predominant P450 enzymes to oxidize EM. The findings helped us to understand the mechanisms of EM-induced hepatotoxicity.

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“…For the quantification of each analyte in MS, the MS1 signal and those of the most significant fragments in MS2 were considered. For aloin A and B, the latter is the ion at m / z 297.2, which results from the loss of [C 4 H 8 O 4 ] [ 26 ]; for aloe emodin it is the ion at m / z 240.1, generated by the loss of [CHO] [ 26 ], along with that at m / z 241.1, due to the loss of [CO]; for emodin, the ion at m / z 241.1, due to the loss of [CO], and that at m / z 225.1, ascribable to the loss of [CHO 2 ] [ 27 , 28 ], were considered. For danthron, the ion at m / z 213.1 generated by the loss of [CO] was considered.…”

Section: Resultsmentioning

confidence: 99%

Development of an LC–DAD–MS-Based Method for the Analysis of Hydroxyanthracene Derivatives in Food Supplements and Plant Materials

Loschi

Faggian²,

Sut

et al. 2022

Molecules

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Products based on plants containing hydroxyanthracene derivatives (HADs)—such as Rheum, Cassia, and Aloe species—are widely used in food supplements or nutraceuticals due to their laxative effects. A more restricted control of HAD contents in food supplements has been implemented by EU Regulation 2021/468, in order to increase the safety of these preparations. Due to their toxicity, aloin A, aloin B, aloe emodin, emodin, and the synthetic derivative danthron have been listed as prohibited substances in food supplements, being tolerated in amounts < 1 mg kg−1 in marketed products. In this work, we report the development of a sensitive and fast LC–DAD–MS-based procedure for the determination of these five compounds in food supplements and plant materials or extracts. The entire procedure includes a simple sample preparation step, where target analytes are concentrated by means of solvent extraction and evaporative concentration (solid samples), or by lyophilisation (liquid samples). The average LOQ of 0.10 mg/L, LOD of 0.03 mg/L, accuracy, and precision with CVs below 12.72 were obtained for the studied analytes. This method is suitable for assessing the compliance of commercial products and raw materials with EU Regulation 2021/468. Furthermore, the proposed method can represent a starting point for the development of a unique and standardised analytical approach for the determination of other HADs under the attention of EU authorities.

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Characterization of emodin metabolites in Raji cells by LC–APCI-MS/MS

Cited by 13 publications

References 42 publications

CYP3A Activation and Glutathione Depletion Aggravate Emodin-Induced Liver Injury

CYP3A Activation and Glutathione Depletion Aggravate Emodin-Induced Liver Injury

Chemical Reactivity of Emodin and Its Oxidative Metabolites to Thiols

Development of an LC–DAD–MS-Based Method for the Analysis of Hydroxyanthracene Derivatives in Food Supplements and Plant Materials

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