Ellipticine oxidation and DNA adduct formation in human hepatocytes is catalyzed by human cytochromes P450 and enhanced by cytochrome b5

Stiborová, Marie; Poljaková, Jitka; Martínková, Eva; Ulrichová, Jitka; Šimánek, Vilı́m; Dvořák, Zdeněk; Frei, Eva

doi:10.1016/j.tox.2012.08.004

Cited by 37 publications

(62 citation statements)

References 36 publications

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“…The predominant mechanisms of ellipticine's biological effects were proposed to be intercalation into DNA (Auclair, 1987;Garbett et al, 2004;Tmejova et al, 2014) and inhibition of topoisomerase II (Auclair, 1987;Garbett et al, 2004;Kizek et al, 2012;Stiborova and Frei, 2014;Stiborová et al, 2011;2015a). We also showed that this antitumor agent forms covalent DNA adducts after metabolic activation by cytochrome P450 (CYP) enzymes and peroxidases (Stiborová et al, , 2003a2003b;2007a;2007b;2012b;Kotrbová et al, 2011), suggesting an additional DNA-damaging effect of ellipticine. This DNA damage has been found to be the major mechanism of ellipticine's antitumor activities 2012b;2014b;2015a;Stiborova and Frei, 2014).…”

Section: Introductionmentioning

confidence: 91%

“…We also showed that this antitumor agent forms covalent DNA adducts after metabolic activation by cytochrome P450 (CYP) enzymes and peroxidases (Stiborová et al, , 2003a2003b;2007a;2007b;2012b;Kotrbová et al, 2011), suggesting an additional DNA-damaging effect of ellipticine. This DNA damage has been found to be the major mechanism of ellipticine's antitumor activities 2012b;2014b;2015a;Stiborova and Frei, 2014).…”

Section: Introductionmentioning

confidence: 91%

“…Of the CYP enzymes, human CYP3A4 is the most active enzyme oxidizing ellipticine to 12hydroxy-and 13-hydroxyellipticine, the reactive metabolites that dissociate to ellipticine-12ylium and ellipticine-13-ylium which form two covalent DNA adducts ( Fig. 1) (Stiborová et al, 2004;2006;2012a;2012b;2014b;2015b). CYP3A4 also generates further metabolites such as 9-hydroxyellipticine, which is considered to be a detoxification metabolite as well as 7-hydroxyellipticine and ellipticine N 2 -oxide (both minor metabolites) (Stiborová et al, 2004;2012a;2012b).…”

Section: Introductionmentioning

confidence: 99%

“…1) (Stiborová et al, 2004;2006;2012a;2012b;2014b;2015b). CYP3A4 also generates further metabolites such as 9-hydroxyellipticine, which is considered to be a detoxification metabolite as well as 7-hydroxyellipticine and ellipticine N 2 -oxide (both minor metabolites) (Stiborová et al, 2004;2012a;2012b). 9-Hydroxyellipticine and 7-hydroxyellipticine are primarily generated by CYP1A1 whereas ellipticine N 2 -oxide is mainly generated by CYP2D6 ( Fig.…”

Section: Introductionmentioning

confidence: 99%

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Ellipticine-loaded apoferritin nanocarrier retains DNA adduct-based cytochrome P450-facilitated toxicity in neuroblastoma cells

et al. 2019

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Although ellipticine (Elli) is an efficient anticancer agent, it exerts several adverse effects. One approach to decrease the adverse effects of drugs is their encapsulation inside a suitable nanocarrier, allowing targeted delivery to tumour tissue whereas avoiding healthy cells. We constructed a nanocarrier from apoferritin (Apo) bearing ellipticine, ApoElli, and subsequently characterized. The nanocarrier exhibits a narrow size distribution suggesting its suitability for entrapping the hydrophobic ellipticine molecule. Ellipticine was released from ApoElli into the water environment under pH 6.5, but only less than 20% was released at pH 7.4. The interaction of ApoElli with microsomal membrane particles containing cytochrome P450 (CYP) biotransformation enzymes accelerated the release of ellipticine from this nanocarrier making it possible to be transferred into this membrane system even at pH 7.4 and facilitating CYPmediated metabolism. Reactive metabolites were formed not only from free ellipticine, but also from ApoElli, and both generated covalent DNA adducts. ApoElli was toxic in UKF-NB-4 neuroblastoma cells, but showed significantly lower cytotoxicity in non-malignant fibroblast HDFn cells. Ellipticine either free or released from ApoElli was concentrated in the nuclei of neuroblastoma cells, concentrations of which being significantly higher in nuclei of UKF-NB-4 than in HDFn cells. In HDFn the higher amounts of ellipticine were sequestrated in lysosomes. The extent of ApoElli entering the nuclei in UKF-NB-4 cells was lower than that of free ellipticine and correlated with the formation of ellipticine-derived DNA adducts. Our study indicates that the ApoElli form of ellipticine seems to be a promising tool for neuroblastoma treatment.

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Section: Introductionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Ellipticine-loaded apoferritin nanocarrier retains DNA adduct-based cytochrome P450-facilitated toxicity in neuroblastoma cells

et al. 2019

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“…Previous biological activities were concerned mainly with the cytotoxic activities of ellipticine [4]. Ellipticine and its derivatives primarily act via combined mechanisms of cell cycle arrest and induction of apoptotic pathways [5] against several cancer cell lines [6][7][8][9]. Herein, we thus report the cytotoxic activity of the ethanolic extract, as well as, the dichloromethane, n-butanol and alkaloidal fractions of O. elliptica leaves and the major isolated alkaloid against MCF-7, MDA-MB-231, VCREMS, hTERT-HME1 cell lines focusing on their cdc25s phosphatase inhibitory activity, along with determination of their antioxidant and in-vivo antiinflammatory activities; in an effort to provide further insight into this plant's profile.…”

Section: Previous Studiesmentioning

confidence: 99%

Chemical and Biological Investigation of Ochrosia elliptica Labill. Cultivated ‎in Egypt

El-Shiekh¹,

Al-Mahdy²,

Hifnawy³

et al. 2017

Rec.Nat.Prod.

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Abstract:The phytochemical investigation of Ochrosia eliptica leaves resulted in isolation and identification of eight compounds; lupeol, lupeol acetate, uvaol, ursolic acid, β-sitosterol glucoside, rutin, 8-methoxy and 9-methoxy ellipticine. The ethanolic extract and fractions were studied for their cytotoxic, antioxidant and antiinflammatory activities. The cytotoxic activity was performed on human mammary adenocarcinoma (MCF7), its multidrug-resistant counterpart (VCREMS), estrogen receptor negative human metastatic breast adenocarcinoma cells (MDA-MB-231) and the non-cancerous, immortalized by telomerase, human breast epithelial cell line (hTERT-HME1). Additionally, the inhibitory potential on Cdc25s proteins was determined. The results showed that the dichloromethane (DCM) fraction and the major alkaloid; 9-methoxyellipticine exhibited high inhibitory activity against all tested cell lines particularly MCF7 and VCREMS cell lines, whereas the DCM fraction showed a significant inhibitory action on Cdc25 A isoform. In contrast, the n-butanol fraction and 9-methoxyellipticine displayed the highest antioxidant potential. The DCM fraction showed significant anti-inflammatory activity compared to indomethacin. This work comprises the first comprehensive work to be conducted on O. elliptica leaves showing its potential in multiple biological activities.

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Human Cytochrome P450 (CYP1A2)‐dsDNA Interaction in situ Evaluation Using a dsDNA‐electrochemical Biosensor

Lopes

Oliveira-Brett

2017

Electroanalysis

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Human cytochrome CYP1A2 is one of the major hepatic cytochrome P450s involved in many drugs metabolism, and chemical carcinogens activation. The CYP1A2‐dsDNA interaction in situ evaluation using a DNA‐electrochemical biosensor and differential pulse voltammetry was investigated. A dsDNA‐electrochemical biosensor showed that CYP1A2 interacted with dsDNA causing conformational changes in the double helix chain and DNA oxidative damage. A preferential interaction between the dsDNA guanosine residues and CYP1A2 was found, as free guanine and 8‐oxoguanine, a DNA oxidative damage biomarker, oxidation peaks were detected. This was confirmed using guanine and adenine homopolynucleotides‐electrochemical biosensors. The CYP1A2‐dsDNA interaction and dsDNA conformation changes was also confirmed by UV‐Vis spectrophotometry.

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Ellipticine oxidation and DNA adduct formation in human hepatocytes is catalyzed by human cytochromes P450 and enhanced by cytochrome b5

Cited by 37 publications

References 36 publications

Ellipticine-loaded apoferritin nanocarrier retains DNA adduct-based cytochrome P450-facilitated toxicity in neuroblastoma cells

Ellipticine-loaded apoferritin nanocarrier retains DNA adduct-based cytochrome P450-facilitated toxicity in neuroblastoma cells

Chemical and Biological Investigation of Ochrosia elliptica Labill. Cultivated ‎in Egypt

Human Cytochrome P450 (CYP1A2)‐dsDNA Interaction in situ Evaluation Using a dsDNA‐electrochemical Biosensor

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