Effects of Oral Anorexiant Sibutramine on the Expression of Cytochromes P450s in Human Hepatocytes and Cancer Cell Lines

Vrzal, Radim; Knoppová, Barbora; Bachleda, Petr; Dvořák, Zdeněk

doi:10.1002/jbt.21516

Cited by 11 publications

(9 citation statements)

References 20 publications

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“…This difference may reflect tissue-specific regulation of CYP3A4 or cell-specific metabolism of benzimidazoles. Indeed, in our previous work, we have observed high constitutive level of CYP3A4 protein in LS174T cells, and no further induction by rifampicin, unlike in HepG2 cells [12]. Expression of CYP3A4 in primary human hepatocytes is affected not only by maternal compounds, but also by their metabolites, since human hepatocytes are highly metabolically competent in vitro model.…”

Section: Discussionmentioning

confidence: 68%

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Omeprazole and Lansoprazole Enantiomers Induce CYP3A4 in Human Hepatocytes and Cell Lines via Glucocorticoid Receptor and Pregnane X Receptor Axis

Novotná

Dvořák

2014

PLoS ONE

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Benzimidazole drugs lansoprazole and omeprazole are used for treatment of various gastrointestinal pathologies. Both compounds cause drug-drug interactions because they activate aryl hydrocarbon receptor and induce CYP1A genes. In the current paper, we examined the effects of lansoprazole and omeprazole enantiomers on the expression of key drug-metabolizing enzyme CYP3A4 in human hepatocytes and human cancer cell lines. Lansoprazole enantiomers, but not omeprazole, were equipotent inducers of CYP3A4 mRNA in HepG2 cells. All forms (S-, R-, rac-) of lansoprazole and omeprazole induced CYP3A4 mRNA and protein in human hepatocytes. The quantitative profiles of CYP3A4 induction by individual forms of lansoprazole and omeprazole exerted enantiospecific patterns. Lansoprazole dose-dependently activated pregnane X receptor PXR in gene reporter assays, and slightly modulated rifampicin-inducible PXR activity, with similar potency for each enantiomer. Omeprazole dose-dependently activated PXR and inhibited rifampicin-inducible PXR activity. The effects of S-omeprazole were much stronger as compared to those of R-omeprazole. All forms of lansoprazole, but not omeprazole, slightly activated glucocorticoid receptor and augmented dexamethasone-induced GR transcriptional activity. Omeprazole and lansoprazole influenced basal and ligand inducible expression of tyrosine aminotransferase, a GR-target gene, in HepG2 cells and human hepatocytes. Overall, we demonstrate here that omeprazole and lansoprazole enantiomers induce CYP3A4 in HepG2 cells and human hepatocytes. The induction comprises differential interactions of omeprazole and lansoprazole with transcriptional regulators PXR and GR, and some of the effects were enantiospecific. The data presented here might be of toxicological and clinical importance, since the effects occurred in therapeutically relevant concentrations.

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Section: Discussionmentioning

confidence: 68%

“…qRT-PCR was carried out using LightCycler FastStart DNA MasterPLUS SYBR Green I (Roche Diagnostic Corporation, Prague, Czech Republic) on a Light Cycler 480 II apparatus (Roche Diagnostic Corporation). CYP3A4, TAT and GAPDH mRNAs were determined as described previously [12]. Measurements were performed in triplicates.…”

Section: Methodsmentioning

confidence: 99%

Omeprazole and Lansoprazole Enantiomers Induce CYP3A4 in Human Hepatocytes and Cell Lines via Glucocorticoid Receptor and Pregnane X Receptor Axis

Novotná

Dvořák

2014

PLoS ONE

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“…The total RNA was isolated by TRI Reagent (Sigma-Aldrich, Prague, Czech Republic) and cDNA was synthesized from 1000 ng of total RNA using M-MuLV Reverse Transcriptase (New England Biolabs, Ipswich, MA) at 42°C for 60 minutes in the presence of random hexamers (New England Biolabs). The levels of CYP1A1 and GAPDH mRNAs were determined using the Light Cycler 480 II apparatus (Roche Diagnostic Corporation, Prague, Czech Republic), as described elsewhere (Vrzal et al, 2013). Measurements were carried out in triplicate.…”

Section: Methodsmentioning

confidence: 99%

Methylindoles and Methoxyindoles are Agonists and Antagonists of Human Aryl Hydrocarbon Receptor

et al. 2018

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Novel methylindoles were identified as endobiotic and xenobiotic ligands of the human aryl hydrocarbon receptor (AhR). We examined the effects of 22 methylated and methoxylated indoles on the transcriptional activity of AhRs. Employing reporter gene assays in AZ-AHR transgenic cells, we determined full agonist, partial agonist, or antagonist activities of tested compounds, having substantially variable EC, IC, and relative efficacies. The most effective agonists ( relative to 5 nM dioxin) of the AhR were 4-Me-indole (134%), 6-Me-indole (91%), and 7-MeO-indole (80%), respectively. The most effective antagonists of the AhR included 3-Me-indole (IC; 19 M), 2,3-diMe-indole (IC; 11 M), and 2,3,7-triMe-indole (IC; 12 M). Reverse transcription polymerase chain reaction analyses of CYP1A1 mRNA in LS180 cells confirmed the data from gene reporter assays. The compound leads, 4-Me-indole and 7-MeO-indole, induced substantial nuclear translocation of the AhR and enriched binding of the AhR to the CYP1A1 promoter, as observed using fluorescent immunohistochemistry and chromatin immunoprecipitation assays, respectively. Molecular modeling and docking studies suggest the agonists and antagonists likely share the same binding pocket but have unique binding modes that code for their affinity. Binding pocket analysis further revealed that 4-methylindole and 7-methoxyindole can simultaneously bind to the pocket and produce synergistic interactions. Together, these data show a dependence on subtle and specific chemical indole structures as AhR modulators and furthermore underscore the importance of complete evaluation of indole compounds as nuclear receptor ligands.

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“…The total RNA was isolated by TRI Reagent ® (Sigma-Aldrich, St. Louis, MO, USA) and cDNA was synthesized using M-MuLV Reverse Transcriptase (New England Biolabs, Ipswich, MA, USA) in the presence of random hexamers (New England Biolabs, USA). The levels of CYP1A1 and glyceraldehyde-3-phosphate dehydrogenase [GAPDH] mRNAs were determined using the Light Cycler ® 480 II apparatus (Roche Diagnostic Corporation, Prague, Czech Republic), as described elsewhere [37]. Measurements were carried out in triplicates.…”

Section: Isolation Of Rna and Qrt-pcrmentioning

confidence: 99%

Antimigraine Drug Avitriptan Is a Ligand and Agonist of Human Aryl Hydrocarbon Receptor that Induces CYP1A1 in Hepatic and Intestinal Cells

Vyhlídalová

Krasulová

Pečinková

et al. 2020

IJMS

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The efforts for therapeutic targeting of the aryl hydrocarbon receptor (AhR) have emerged in recent years. We investigated the effects of available antimigraine triptan drugs, having an indole core in their structure, on AhR signaling in human hepatic and intestinal cells. Activation of AhR in reporter gene assays was observed for Avitriptan and to a lesser extent for Donitriptan, while other triptans were very weak or no activators of AhR. Using competitive binding assay and by homology docking, we identified Avitriptan as a low-affinity ligand of AhR. Avitriptan triggered nuclear translocation of AhR and increased binding of AhR in CYP1A1 promotor DNA, as revealed by immune-fluorescence microscopy and chromatin immune-precipitation assay, respectively. Strong induction of CYP1A1 mRNA was achieved by Avitriptan in wild type but not in AhR-knockout, immortalized human hepatocytes, implying that induction of CYP1A1 is AhR-dependent. Increased levels of CYP1A1 mRNA by Avitriptan were observed in human colon carcinoma cells LS180 but not in primary cultures of human hepatocytes. Collectively, we show that Avitriptan is a weak ligand and activator of human AhR, which induces the expression of CYP1A1 in a cell-type specific manner. Our data warrant the potential off-label therapeutic application of Avitriptan as an AhR-agonist drug.

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Effects of Oral Anorexiant Sibutramine on the Expression of Cytochromes P450s in Human Hepatocytes and Cancer Cell Lines

Cited by 11 publications

References 20 publications

Omeprazole and Lansoprazole Enantiomers Induce CYP3A4 in Human Hepatocytes and Cell Lines via Glucocorticoid Receptor and Pregnane X Receptor Axis

Omeprazole and Lansoprazole Enantiomers Induce CYP3A4 in Human Hepatocytes and Cell Lines via Glucocorticoid Receptor and Pregnane X Receptor Axis

Methylindoles and Methoxyindoles are Agonists and Antagonists of Human Aryl Hydrocarbon Receptor

Antimigraine Drug Avitriptan Is a Ligand and Agonist of Human Aryl Hydrocarbon Receptor that Induces CYP1A1 in Hepatic and Intestinal Cells

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