Evaluation of Genotoxicity and Toxicity of Annona muricata L. Seeds and In Silico Studies

Ferreira, Gleison Gonçalves; Quaresma, Ana Carolina Sousa; Brandão, Dayse Lúcia do Nascimento; Marinho, Andrey Moacir do Rosário; Siqueira, José Edson de Sousa; Correa, Kamila Leal; Júnior, José Otávio Carréra Silva; Percário, Sandro; Dolabela, Maria Fâni

doi:10.3390/molecules28010231

Cited by 7 publications

(9 citation statements)

References 35 publications

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“…The roots were immersed in hydrochloric acid to 1M for 15 min for hydrolysis, followed by 3 more washes in distilled water (5 min each). The roots were stained with 2% acetic orcein for a period of 10 min [ 47 ].…”

Section: Methodsmentioning

confidence: 99%

Cytotoxicity and Genotoxicity Evaluation of Zanthoxylum rhoifolium Lam and In Silico Studies of Its Alkaloids

et al. 2023

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The alkaloids isolated from Zanthoxylum rhoifolium have demonstrated great pharmacological potential; however, the toxic profiles of these extracts and fractions are still not well elucidated. This study evaluated the toxicity of the ethanol extract (EEZR) and neutral (FNZR) and alkaloid (FAZR) fractions. Chemical characterization was performed by chromatographic methods: thin-layer chromatography (TLC) and high-performance liquid chromatography coupled with diode array detection (HPLC–DAD). The cytotoxicity of the samples was evaluated in human hepatocellular carcinoma (HepG2) cells using the cell viability method (MTT) and mutagenicity by the Allium cepa assay (ACA). Alkaloids isolated from the species were selected for toxicity prediction using preADMET and PROTOX. The molecular docking of the topoisomerase II protein (TOPOII) was used to investigate the mechanism of cell damage. In the EEZR, FNZR, and FAZR, the presence of alkaloids was detected in TCL and HPLC–DAD analyses. These samples showed a 50% inhibitory concentration (IC50) greater than 400 μg/mL in HepG2 cells. In ACA, time- and concentration-dependent changes were observed, with a significant reduction in the mitotic index and an increase in chromosomal aberrations for all samples. Nuclear sprouts and a micronucleus of the positive control (PC) were observed at 10 µg/mL and in the FAZR at 30 µg/mL; a chromosomal bridge in FNZR was observed at 105 µg/mL, CP at a concentration of 40 µg/mL, and nuclear bud and mitotic abnormalities in the EEZR were observed at 170 µg/mL. The alkaloids with a benzophenanthridine were selected for the in silico study, as structural alterations demonstrated certain toxic effects. Molecular docking with topo II demonstrated that all alkaloids bind to the protein. In summary, the fractionation of Z. rhoifolium did not interfere with toxicity; it seems that alkaloids with a benzophenanthridine nucleus may be involved in this toxicity.

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Section: Methodsmentioning

confidence: 99%

Cytotoxicity and Genotoxicity Evaluation of Zanthoxylum rhoifolium Lam and In Silico Studies of Its Alkaloids

et al. 2023

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“…Chemical studies carried out on A. muricata led to the isolation of alkaloids, acetogenins, flavonoids, phenols, cyclopeptides ( Moghadamtousi et al, 2015 ; Coria-téllez and Ana, 2018 ; Ferreira, 2022 ), carotenoids, and amides ( Vijayameena et al, 2013 ). The acetogenins were characterized as majority compounds on this species ( Mutakin et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

“…Acetogenins, or polyketides, are metabolites derived from fatty acids. They have a long aliphatic chain of 35–38 carbons linked to a g-lactone ring, terminally substituted by β-unsaturated methyl, with tetrahydrofurans (THF) located along the hydrocarbon chain ( Mutakin et al, 2022 ), being the presence of the hydroxyl groups, THF ring and the α, β-unsaturated y-lactone subunit responsible for producing the toxic effect of these compounds ( Ferreira, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

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In silico studies on cytotoxicity and antitumoral activity of acetogenins from Annona muricata L

Fallon Adido,

Silva Chagas,

Ferreira

et al. 2023

Front. Chem.

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As life expectancy increases, the number of people affected by cancer is increasing. The available drugs still cause several adverse reactions, and it is important to look for less toxic drugs that act on resistant cancers. The present study evaluated the antitumor potential of acetogenins. Through a literature review, 44 acetogenins isolated from Annona muricata were selected and subjected to in silico studies to predict the physicochemical properties, pharmacokinetics (Preadmet and Admet lab), toxicity (Preadmet and Protox II) and molecular docking in caspase 3 (DockThor). For muricatacin, a literature review was carried out for antitumor activity and cytotoxicity. Only muricatacin met all physicochemical criteria, while all compounds showed high cutaneous and intestinal absorption (HIA), moderate permeability in Madin-Darby canine kidney and Caco2 cells, strongly bound plasma proteins, freely crossed the blood-brain barrier, inhibited CYP2C19, CYP2C9 and CYP3A4 and have an affinity for CYP3A4, being metabolized by it, an undesirable characteristic for antitumor drugs. All compounds were toxic in at least one model, while compound 28 was not carcinogenic in rats and mice. Compounds 13, 14, 15, 16, 17 and 28 were selected for molecular docking into Caspase 3. Docking showed hydrophobic interactions, hydrogen and covalent bonds performed to maintain the stability of caspase 3, and cis-uvariamicin IV stood out more through the energies and chemical bonds of this parameter. The chloroform fraction from the methanolic extract of the seeds showed activity against triple-negative breast cancer, both in vitro and in vivo, and only muricatacin has studies in which the antitumor activity was evaluated in vitro and showed to be very promising. In summary, muricatacin and cis-uvariamicin IV appear to be very promising as antitumors, especially cis-uvariamicin IV.

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“…One of the studies testified that high intake of soursop leaves can cause extremely low blood glucose level [ 7 ]. One of the sources of toxic compounds that produce the toxicity effect is annonacin, which belongs to acetogenins group [ 8 ]. A comprehensive understanding of its toxicological effects remains limited.…”

Section: Introductionmentioning

confidence: 99%

Assessing the Acute Toxicological Effects of Annona muricata Leaf Ethanol Extract on Rats: Biochemical, Histopathological, and Metabolomics Analyses

Zubaidi

Qadi

Maarof

et al. 2023

Toxics

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Annona muricata is a common plant used in Africa and South America to manage various types of disease. However, there is insufficient toxicological information or published standard available regarding repeated dose animal toxicity data. As part of the safety assessment, we exposed Sprague Dawley rats to an acute oral toxicity of A. muricata. The intent of the current study was to use advanced proton nuclear magnetic resonance (1H NMR) in serum and urinary metabolomics evaluation techniques to provide the in vivo acute toxicological profile of A. muricata leaf ethanol extract in accordance with the Organization for Economic Co-operation and Development’s (OECD) 423 guidelines. A single 2000 mg/kg dose of A. muricata leaf ethanol extract was administered to Sprague Dawley rats over an observational period of 14 days. The toxicity evaluation (physical and behavior observation, body weight, renal function test, liver function test and 1H NMR analysis) showed no abnormal toxicity. Histopathological analysis manifested mild changes, i.e., the treated kidney manifested mild hypercellularity of mesangial cells and mild red blood cell congestion. In addition, there was mild hemorrhage into tissue with scattered inflammatory cells and mild dilated central vein with fibrosis in the liver. However, the changes were very mild and not significant which correlate with other analyses conducted in this study (biochemical test and 1H NMR metabolomic analysis). On the other hand, urinary 1H NMR analysis collected on day 15 revealed high similarity on the metabolite variations for both untreated and treated groups. Importantly, the outcomes suggest that A. muricata leaf ethanol extract can be safely consumed at a dose of 2000 mg/kg and the LD50 must be more than 2000 mg/kg.

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Evaluation of Genotoxicity and Toxicity of Annona muricata L. Seeds and In Silico Studies

Cited by 7 publications

References 35 publications

Cytotoxicity and Genotoxicity Evaluation of Zanthoxylum rhoifolium Lam and In Silico Studies of Its Alkaloids

Cytotoxicity and Genotoxicity Evaluation of Zanthoxylum rhoifolium Lam and In Silico Studies of Its Alkaloids

In silico studies on cytotoxicity and antitumoral activity of acetogenins from Annona muricata L

Assessing the Acute Toxicological Effects of Annona muricata Leaf Ethanol Extract on Rats: Biochemical, Histopathological, and Metabolomics Analyses

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