Pyrrolizidine alkaloid clivorine induces apoptosis in human normal liver L-02 cells and reduces the expression of p53 protein

Ji, Lili; Zhang, Mian; Sheng, Yuchen; Wang, Zhengtao

doi:10.1016/j.tiv.2004.06.003

Cited by 38 publications

(15 citation statements)

References 24 publications

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“…See DOI: 10.1039/ c4tx00246f a Ma and colleagues, and some other researchers' studies, showed that this cell line is suitable for the analysis of druginduced hepatotoxicity. [20][21][22] The primary goal of this study was to investigate emodininduced cytotoxicity in human normal liver cells (L-02), to assess the toxicity-related metabolic pathways and to explore toxicity-related mechanisms. Cell viability was determined using the MTT assay.…”

Section: Introductionmentioning

confidence: 99%

Metabolomic profiling of emodin-induced cytotoxicity in human liver cells and mechanistic study

Liu

et al. 2015

Toxicol. Res.

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Emodin is one of the most representative natural anthraquinone polyphenols and the liver is one of the major target organs for drug-induced toxicology. The hepatocyte is frequently affected due to its role in emodin metabolism and accumulation. Although the hepatotoxicity of emodin has been reported, its toxicological mechanism is still unclear. The purpose of the present study was to evaluate the cytotoxicity of emodin in cultured human normal liver cells (L-02), to investigate the toxicity-related metabolic pathways and to predict the possible toxicity mechanism. Cell viability was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cytotoxicity tests demonstrated a concentration-dependent toxic effect of emodin on L-02 cells. Cells were treated for 48 h with low, medium and high doses of emodin, respectively, and then subjected to metabolomics analysis using ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS). Intracellular metabolomics analysis revealed that emodin significantly disturbed cellular glutathione and fatty acid metabolism. In addition, an emodin-cysteine adduct was identified in cell culture medium, and its level increased with increasing concentrations of emodin. The possible relationship among metabolic disorders, adduct formation and emodin hepatotoxicity was also discussed. This study provides new insight into the cytotoxicity of emodin on metabolic pathways in human liver cells.

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Section: Introductionmentioning

confidence: 99%

Metabolomic profiling of emodin-induced cytotoxicity in human liver cells and mechanistic study

Liu

et al. 2015

Toxicol. Res.

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“…Hepatic metabolic activation of PAs to electrophilic pyrrolic metabolites has been suggested to initiate the development of PA‐induced liver injury . Apoptosis and oxidative injury were also involved in toxicity induced by PAs . PAs usually exist in trace amounts and occur as isomers in herbs, which increases the difficulty of purifying individual PAs and hinders the investigations on their toxic mechanism and treatments.…”

Section: Introductionmentioning

confidence: 99%

Mass-spectrometry-directed analysis and purification of pyrrolizidine alkaloidcis/transisomers inGynura japonica

et al. 2014

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Pyrrolizidine alkaloids are highly hepatotoxic natural chemicals that produce irreversible chronic and acute hepatotoxic effects on human beings. Purification of large amounts of pyrrolizidine alkaloids is necessary for toxicity studies. In this study, an efficient method for targeted analysis and purification of pyrrolizidine alkaloid cis/trans isomers from herbal materials was developed for the first time. Targeted analysis of the hepatotoxic pyrrolizidine alkaloids was performed by liquid chromatography with tandem mass spectrometry (precursor ion scan and daughter ion scan), and the purification of pyrrolizidine alkaloids was achieved with a mass-directed auto purification system. The extraction and preparative liquid chromatography conditions were optimized. The developed method was applied to analysis of Gynura japonica (Thunb.) Juel., a herbal medicine traditionally used for detumescence and relieving pain but is potentially hepatotoxic as it contains pyrrolizidine alkaloids. Twelve pyrrolizidine alkaloids (six cis/trans isomer pairs) were identified with reference compounds or characterized by liquid chromatography with tandem mass spectrometry, and five individual pyrrolizidine alkaloids, including (E)-seneciphylline, seneciphylline, integerrimine, senecionine, and seneciphyllinine, were prepared from G. japonica roots with high efficiency. The results of this work provide a new technique for the preparation of large amounts of pyrrolizidine alkaloid reference substances, which will also benefit toxicological studies of pyrrolizidine alkaloids and treatments for pyrrolizidine alkaloid-induced toxicity.

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“…One proposed mechanism implicates PAs in inhibiting hepatocyte proliferation and inducing cell death is by decreasing the level of Bcl-x, an anti-apoptotic protein, and increasing the level of Bax, a proapoptotic protein that enhances the release of cytochrome c from the mitochondria for apoptosis (123). Another proposed mechanism to explain PAinduced apoptosis involves reduced p53expression, which is independent from Bcl expression (124). Zuckerman et al have conducted an in vitro study and demonstrated that toxic PAs not only induce apoptosis, but also clump the tubulin cytoskeleton at relatively low concentration, and lead to necrotic cell bodies (125).…”

Section: Hepatic Sinusoidal Obstruction Syndromementioning

confidence: 99%

Hepatotoxicity of Pyrrolizidine Alkaloids

et al. 2015

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PURPOSE: This article aimed 1) to review herbal medicine containing pyrrolizidine alkaloids (PA)-induced toxicities of the liver; 2) to encourage the recognition and prevention of common problems encountered when using complementary and alternative medicine and 3) to review the toxic effects of herbal remedies containing PAs. DESIGN AND METHODS: We performed a systematic literature search using the PubMed and Google Scholar engines. The search was not restricted to languages. We also provide an interpretation of the data. CONCLUSIONS: Herbal remedies containing PAs can induce liver damage, including hepato- sinusoidal obstruction syndrome or veno-occlusive disease. Preventing overdose and monitoring long-term use of such remedies may avoid glutathione depletion leading to mitochondrial injury, and therefore avoid liver cell damage. Moreover, immediately stopping the herbal medication prevents further harm to the liver. Chronic consumption of hepatotoxicants can lead to cancer formation and promotion. The role of active metabolites in PA-induced liver toxicity and their mechanism of action require further investigation. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Pyrrolizidine alkaloid clivorine induces apoptosis in human normal liver L-02 cells and reduces the expression of p53 protein

Cited by 38 publications

References 24 publications

Metabolomic profiling of emodin-induced cytotoxicity in human liver cells and mechanistic study

Metabolomic profiling of emodin-induced cytotoxicity in human liver cells and mechanistic study

Mass-spectrometry-directed analysis and purification of pyrrolizidine alkaloidcis/transisomers inGynura japonica

Hepatotoxicity of Pyrrolizidine Alkaloids

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