Cytotoxicity of safrole in HepaRG cells: studies on the role of CYP1A2-mediated ortho-quinone metabolic activation

Hu, Linlin; Wu, Fei; He, Jie; Zhong, Lingjun; Song, Yifan; Shao, Hua

doi:10.1080/00498254.2019.1590882

Cited by 11 publications

(6 citation statements)

References 36 publications

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“…Similarly, the human immortalized hepatocytes-HepaRG are widely employed as models for various in vitro assays, including toxicity evaluations (Klein et al, 2014;Rednic et al, 2022). Advantageously, the HepaRG cell line maintains the major hepatic-like functions (as drug transporters and enzymes involved in xenobiotics metabolism), have the ability to differentiate into hepatocyte-like and biliary-like cells (Tascher et al, 2019;Young and Young, 2019) and represent a powerful alternative to primary human hepatocytes with higher availability and reproducibility (Rednic et al, 2022;Hu et al, 2019;Blidisel et al, 2021). HaCaT cells are spontaneous immortalized human keratinocytes with a long life in culture that express basal properties and could be differentiated under the effects of different inducers as Ca 2+ and high cell density.…”

Section: Discussionmentioning

confidence: 99%

Rutin bioconjugates as potential nutraceutical prodrugs: An in vitro and in ovo toxicological screening

et al. 2022

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Rutin (RUT) is considered one the most attractive flavonoids from a therapeutic perspective due to its multispectral pharmacological activities including antiradical, anti-inflammatory, antiproliferative, and antimetastatic among others. Still, this compound presents a low bioavailability what narrows its clinical applications. To overcome this inconvenience, the current paper was focused on the synthesis, characterization, and toxicological assessment of two RUT bioconjugates obtained by enzymatic esterification with oleic acid (OA) and linoleic acid (LA)—rutin oleate (RUT-O) and rutin linoleate (RUT-L), as flavonoid precursors with improved physicochemical and biological properties. Following the enzymatic synthesis in the presence of Novozyme® 435, the two bioconjugates were obtained, their formation being confirmed by RAMAN and FT-IR spectroscopy. The in vitro and in ovo toxicological assessment of RUT bioconjugates (1–100 µM) was performed using 2D consecrated cell lines (cardiomyoblasts - H9c2(2-1), hepatocytes—HepaRG, and keratinocytes—HaCaT), 3D reconstructed human epidermis tissue (EpiDerm™), and chick chorioallantoic membranes, respectively. The results obtained were test compound, concentration—and cell-type dependent, as follows: RUT-O reduced the viability of H9c2(2-1), HepaRG, and HaCaT cells at 100 µM (to 77.53%, 83.17%, and 78.32%, respectively), and induced cell rounding and floating, as well as apoptotic-like features in the nuclei of all cell lines, whereas RUT-L exerted no signs of cytotoxicity in all cell lines in terms of cell viability, morphology, and nuclear integrity. Both RUT esters impaired the migration of HepaRG cells (at 25 µM) and lack irritative potential (at 100 µM) in vitro (tissue viability >50%) and in ovo (irritation scores of 0.70 for RUT-O, and 0.49 for RUT-L, respectively). Computational predictions revealed an increased lipophilicity, and reduced solubility, drug-likeness and drug score of RUT-O and RUT-L compared to their parent compounds—RUT, OA, and LA. In conclusion, we report a favorable toxicological profile for RUT-L, while RUT-O is dosage-limited since at high concentrations were noticed cytotoxic effects.

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Section: Discussionmentioning

confidence: 99%

Rutin bioconjugates as potential nutraceutical prodrugs: An in vitro and in ovo toxicological screening

et al. 2022

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“…Thereafter, the cells employed for this study were cultured at low passages to avoid any lack of reliability. HepaRG is an immortalized human hepatic progenitor cell line recently emerging as a useful in vitro model for toxicological evaluations, representing one of the most employed cell lines for the study of drug-induced toxicity [28][29][30]. Compared to primary hepatocytes, HepaRG cells are more advantageous in terms of availability and reproducibility [28].…”

Section: Discussionmentioning

confidence: 99%

In Vitro Toxicological Profile of Labetalol-Folic Acid/Folate Co-Administration in H9c2(2-1) and HepaRG Cells

et al. 2022

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Background and Objectives: The consumption of dietary supplements has increased over the last decades among pregnant women, becoming an efficient resource of micronutrients able to satisfy their nutritional needs during pregnancy. Furthermore, gestational drug administration might be necessary to treat several pregnancy complications such as hypertension. Folic acid (FA) and folate (FT) supplementation is highly recommended by clinicians during pregnancy, especially for preventing neural tube birth defects, while labetalol (LB) is a β-blocker commonly administered as a safe option for the treatment of pregnancy-related hypertension. Currently, the possible toxicity resulting from the co-administration of FA/FT and LB has not been fully evaluated. In light of these considerations, the current study was aimed at investigating the possible in vitro cardio- and hepato-toxicity of LB-FA and LB-FT associations. Materials and Methods: Five different concentrations of LB, FA, FT, and their combination were used in myoblasts and hepatocytes in order to assess cell viability, cell morphology, and wound regeneration. Results: The results indicate no significant alterations in terms of cell viability and morphology in myoblasts (H9c2(2-1)) and hepatocytes (HepaRG) following a 72-h treatment, apart from a decrease in the percentage of viable H9c2(2-1) cells (~67%) treated with LB 150 nM–FT 50 nM. Additionally, LB (50 and 150 nM)–FA (0.2 nM) exerted an efficient wound regenerating potential in H9c2(2-1) myoblasts (wound healing rates were >80%, compared to the control at 66%), while LB-FT (at all tested concentrations) induced no significant impairment to their migration. Conclusions: Overall, our findings indicate that LB-FA and LB-FT combinations lack cytotoxicity in vitro. Moreover, beneficial effects were noticed on H9c2(2-1) cell viability and migration from LB-FA/FT administration, which should be further explored.

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“…The researchers further identified the RMs (quinones and their tautomers) of SFO in HLM, indicating that SFO may undergo a CYP-mediated MBI process to produce RMs, resulting in the subsequent inhibition of enzyme activity and hepatotoxicity. Another similar study [36] explored the hepatotoxic mechanism of SFO in HepaRG cells, finding that SFO's toxicity was increased when CYP1A2 was activated by omeprazole whereas decreased upon CYP1A2 inhibition by a-naphthoflavone (α-NAP), which was linked to the formation of RMs. Moreover, the depletion of cellular glutathione (GSH) increased SFO toxicity, confirming that SFO hepatotoxicity is likely mediated by ortho-quinone RMs, in which CYP1A2 plays a central role.…”

Section: Formation Of Reactive Metabolites (Rms)mentioning

confidence: 99%

Research progress on the toxicity of Asari Radix et Rhizoma

Li,

Chen,

Duan

et al. 2024

Acupuncture and Herbal Medicine

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Asari Radix et Rhizoma (ARR), also known as Xixin, has been broadly used as a traditional herbal medicine in East Asia and is an important component of classic prescriptions, including mahuang fuzi xixin decoction. It was initially classified as a “top grade” herb in ancient Chinese Pharmacopeia, Shennong’s Materia Medica. Volatile oils, lignans, fatty acids, flavonoids, and nitrogen-containing compounds are the main ARR components. Previous pharmacological studies have shown that ARR exerts beneficial effects in humans for treating headaches, toothaches, and several inflammatory diseases by dispelling wind and cold, alleviating pain, and eliminating phlegm. However, “the dosage of ARR should not exceed one coin (approximately 3.75 grams)”, as stated in Shizhen Li’s Compendium of Materia, emphasized the considerable ARR toxicity and significantly constrained its clinical application. This review aimed to consolidate recent advancements in the understanding of the toxic ARR components. Additionally, we provide an overview of the hepatotoxicity, genotoxicity, neurotoxicity, and pulmonary toxicity of ARR and discuss the underlying molecular mechanisms. This study reviews the limitations of current studies and enhances our understanding of the toxic effects of ARR from the perspective of its toxic components and mechanisms, thereby providing a theoretical basis for the rational clinical practice of ARR-based medications.

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Cytotoxicity of safrole in HepaRG cells: studies on the role of CYP1A2-mediated ortho-quinone metabolic activation

Cited by 11 publications

References 36 publications

Rutin bioconjugates as potential nutraceutical prodrugs: An in vitro and in ovo toxicological screening

Rutin bioconjugates as potential nutraceutical prodrugs: An in vitro and in ovo toxicological screening

In Vitro Toxicological Profile of Labetalol-Folic Acid/Folate Co-Administration in H9c2(2-1) and HepaRG Cells

Research progress on the toxicity of Asari Radix et Rhizoma

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