Impact of Inflammation on Chlorpromazine-Induced Cytotoxicity and Cholestatic Features in HepaRG Cells

Azzi, Pamela Bachour-El; Sharanek, Ahmad; Abdel-Razzak, Ziad; Anthérieu, Sébastien; Al-Attrache, Houssein; Savary, Camille; Lepage, Sylvie; Morel, Isabelle; Labbe, Gilles; Guguen‐Guillouzo, Christiane

doi:10.1124/dmd.114.058123

Cited by 30 publications

(25 citation statements)

References 37 publications

(38 reference statements)

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“…These data are in agreement with previous studies concerning the noncytotoxic nature of the carrier (PC) and loaded flavonoids. 62,63 The microscopic images of HepaRG cells treated with higher concentration (200 µg/mL) of flavonosomes were shown in Figure 8C and D. The images support the obtained cytotoxicity results, whereby after 24 hours treatment with the various formulated flavonosomes revealed no signs of toxicity, which was confirmed by the absence of intracytoplasmic vesicles formation as reported in previous studies; 31,64,65 in contrast, the flavonosome treated HepaRG cells inclusive of both hepatocyte-like cells (H) and epithelium-like cells (I) remain healthy and intact similar to the morphology and architecture of untreated control cells (Figure 8C and D). This strongly suggests that flavonosomes could play an effective hepatosupplemental/hepatoprotective role.…”

supporting

confidence: 72%

Optimization, formulation, and characterization of multiflavonoids-loaded flavanosome by bulk or sequential technique

Karthivashan¹,

Kura²,

Abas³

et al. 2016

IJN

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This study involves adaptation of bulk or sequential technique to load multiple flavonoids in a single phytosome, which can be termed as “flavonosome”. Three widely established and therapeutically valuable flavonoids, such as quercetin (Q), kaempferol (K), and apigenin (A), were quantified in the ethyl acetate fraction of Moringa oleifera leaves extract and were commercially obtained and incorporated in a single flavonosome (QKA–phosphatidylcholine) through four different methods of synthesis – bulk (M1) and serialized (M2) co-sonication and bulk (M3) and sequential (M4) co-loading. The study also established an optimal formulation method based on screening the synthesized flavonosomes with respect to their size, charge, polydispersity index, morphology, drug–carrier interaction, antioxidant potential through in vitro 1,1-diphenyl-2-picrylhydrazyl kinetics, and cytotoxicity evaluation against human hepatoma cell line (HepaRG). Furthermore, entrapment and loading efficiency of flavonoids in the optimal flavonosome have been identified. Among the four synthesis methods, sequential loading technique has been optimized as the best method for the synthesis of QKA–phosphatidylcholine flavonosome, which revealed an average diameter of 375.93±33.61 nm, with a zeta potential of −39.07±3.55 mV, and the entrapment efficiency was >98% for all the flavonoids, whereas the drug-loading capacity of Q, K, and A was 31.63%±0.17%, 34.51%±2.07%, and 31.79%±0.01%, respectively. The in vitro 1,1-diphenyl-2-picrylhydrazyl kinetics of the flavonoids indirectly depicts the release kinetic behavior of the flavonoids from the carrier. The QKA-loaded flavonosome had no indication of toxicity toward human hepatoma cell line as shown by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide result, wherein even at the higher concentration of 200 µg/mL, the flavonosomes exert >85% of cell viability. These results suggest that sequential loading technique may be a promising nanodrug delivery system for loading multiflavonoids in a single entity with sustained activity as an antioxidant, hepatoprotective, and hepatosupplement candidate.

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supporting

confidence: 72%

Optimization, formulation, and characterization of multiflavonoids-loaded flavanosome by bulk or sequential technique

Karthivashan¹,

Kura²,

Abas³

et al. 2016

IJN

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“…Several investigations indicated that the threshold for hepatotoxicity from many xenobiotics was lowered by co-exposure to LPS. 22,23,[40][41][42][43] The ability of LPS to stimulate an inflammatory response may account for its pathogenicity in the liver. LPS is a potent activator of liver tissue macrophages (Kupffer cells) through toll-like receptors (TLRs) (Figure 6).…”

Section: Discussionmentioning

confidence: 99%

Concurrent Inflammation Augments Antimalarial Drugs-Induced Liver Injury in Rats

et al. 2016

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“…Studies investigating the effects of inflammatory signaling in PHH often focused on particular groups of drug-metabolizing enzymes (e.g., P450s) (Aitken et al, 2006) or drug transporters (Le Vee et al, 2008). In HepaRG cells, an induction of the APR was previously shown by increased C-reactive protein (CRP) expression upon lipopolysaccharide or IL-6 stimulation, simultaneously causing a suppression of CYP3A4 or CYP1A2 and CYP3A4 expression, respectively (Aninat et al, 2008;Bachour-El Azzi et al, 2014). Furthermore, it was shown that IL-1b leads to downregulation of organic anion transporter expression (Le Vee et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

A Systematic Comparison of the Impact of Inflammatory Signaling on Absorption, Distribution, Metabolism, and Excretion Gene Expression and Activity in Primary Human Hepatocytes and HepaRG Cells

et al. 2014

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Inflammatory processes are associated with compromised metabolism and elimination of drugs in the liver, largely mediated by proinflammatory cytokines, such as interleukin-6. The Hepa-RG cell line is an established surrogate for primary human hepatocytes (PHH) in drug metabolism and toxicity studies. However, the impact of inflammatory signaling on HepaRG cells has not been well characterized. In this study, the response of primary human hepatocytes and HepaRG cells to interleukin (IL)-6 was comparatively analyzed. For this purpose, broad-spectrum gene expression profiling, including acute-phase response genes and a large panel of drug-metabolizing enzyme and transporter (DMET) genes as well as their modifiers and regulators, was conducted in combination with cytochrome P450 (P450) activity measurements. Exposure of PHH and HepaRG cells to IL-6 resulted in highly similar coordinated reduction of DMET mRNA, including major ATP-binding cassette transporters (ABCs), P450s, glutathione S-transferases (GSTs), uridine diphosphate glucuronosyltransferases (UGTs), and solute carriers (SLCs). Enzyme activities of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4 were reduced upon 48-72 hours exposure to IL-6 in PHH and HepaRG. However, although these effects were not significant in PHH due to large interindividual donor variability, the impact on HepaRG was more pronounced and highly significant, thus emphasizing the advantage of HepaRG as a more reproducible model system. Exposure of HepaRG cells to interleukin-1b and tumor necrosis factor a resulted in similar effects on gene expression and enzyme activities. The present study emphasizes the role of proinflammatory cytokines in the regulation of drug metabolism and supports the use of HepaRG in lieu of PHH to minimize subject variability.

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Impact of Inflammation on Chlorpromazine-Induced Cytotoxicity and Cholestatic Features in HepaRG Cells

Cited by 30 publications

References 37 publications

Optimization, formulation, and characterization of multiflavonoids-loaded flavanosome by bulk or sequential technique

Optimization, formulation, and characterization of multiflavonoids-loaded flavanosome by bulk or sequential technique

Concurrent Inflammation Augments Antimalarial Drugs-Induced Liver Injury in Rats

A Systematic Comparison of the Impact of Inflammatory Signaling on Absorption, Distribution, Metabolism, and Excretion Gene Expression and Activity in Primary Human Hepatocytes and HepaRG Cells

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