β2-adrenergic receptor-mediated in vitro regulation of human hepatic drug transporter expression by epinephrine

Mayati, Abdullah; Moreau, A; Denizot, Claire; Stieger, Bruno; Parmentier, Yannick; Fardel, Olivier

doi:10.1016/j.ejps.2017.06.010

Cited by 8 publications

(11 citation statements)

References 64 publications

(63 reference statements)

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“…In agreement with this assertion, the amount of 18S rRNA in proliferating and differentiated HepaG cells did not vary, i.e., the C t numbers determined from qPCR assays were similar in these cells (Figure S1). Data of qPCR experiments were finally commonly expressed in arbitrary units relatively to 18S rRNA or as fold change comparatively to control untreated cells, as previously reported [29].…”

Section: Methodsmentioning

confidence: 99%

mRNA Expression and Activity of Nucleoside Transporters in Human Hepatoma HepaRG Cells

et al. 2018

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The HepaRG cell line is a highly differentiated human hepatoma cell line, displaying the expression of various drug transporters. However, functional expression of nucleoside transporters remains poorly characterized in HepaRG cells, although these transporters play a key role in hepatic uptake of antiviral and anticancer drugs. The present study was, therefore, designed to characterize the expression, activity and regulation of equilibrative (ENT) and concentrative (CNT) nucleoside transporter isoforms in differentiated HepaRG cells. These cells were found to exhibit a profile of nucleoside transporter mRNAs similar to that found in human hepatocytes, i.e., notable expression of ENT1, ENT2 and CNT1, with very low or no expression of CNT2 and CNT3. ENT1 activity was, next, demonstrated to be the main uridine transport activity present in HepaRG cells, like in cultured human hepatocytes. Various physiological factors, such as protein kinase C (PKC) activation or treatment by inflammatory cytokines or hepatocyte growth factor (HGF), were additionally found to regulate expression of ENT1, ENT2 and CNT1; PKC activation and HGF notably concomitantly induced mRNA expression and activity of ENT1 in HepaRG cells. Overall, these data suggest that HepaRG cells may be useful for analyzing cellular pharmacokinetics of nucleoside-like drugs in human hepatic cells, especially of those handled by ENT1.

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Section: Methodsmentioning

confidence: 99%

mRNA Expression and Activity of Nucleoside Transporters in Human Hepatoma HepaRG Cells

et al. 2018

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“…Similarly, modulation by fluctuation of cAMP levels, one of the major downstream processes that could be involved after mPR activation, has been reported for P-gp [20], MRP2 [21] and MRP3 [22]. However, a potential association between this receptor and transporter regulation has not been investigated before.…”

Section: Introductionmentioning

confidence: 90%

Biphasic modulation of cAMP levels by the contraceptive nomegestrol acetate. Impact on P-glycoprotein expression and activity in hepatic cells

Tocchetti

Domínguez

Zecchinati

et al. 2018

Biochemical Pharmacology

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ABC transporters are key players in drug excretion with alterations in their expression and activity by therapeutic agents potentially leading to drug-drug interactions. The interaction potential of nomegestrol acetate (NMGA), a synthetic progestogen increasingly used as oral contraceptive, had never been explored. In this work we evaluated (1) the effect of NMGA on ABC transporters in the human hepatic cell line HepG2 and (2) the underlying molecular mechanism. NMGA (5, 50 and 500 nM) increased P-glycoprotein (P-gp) expression at both protein and mRNA levels and reduced intracellular calcein accumulation, indicating an increase also in transporter activity. This up-regulation of P-gp was corroborated in Huh7 cells and was independent of the classical progesterone receptor. Instead, using a siRNA-mediated silencing approach, we demonstrated the involvement of membrane progesterone receptor α. Moreover, we found that the activation of this receptor by NMGA led to a falling-rising profile in intracellular cAMP levels and protein kinase A activity over time, ultimately leading to transcriptional P-gp up-regulation. Finally, we identified inhibitory G protein and phosphodiesterases as mediators of this novel biphasic modulation. These results demonstrate the ability of NMGA to selectively up-regulate hepatic P-gp expression and activity and constitute the first report of ABC transporter modulation by membrane progesterone receptor α. If a similar regulation took place in vivo, decreased bioavailability and therapeutic efficacy of NMGA-coadministered P-gp substrates could be expected. This holds special importance considering long-term administration of NMGA and broad substrate specificity of P-gp.

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“…Regarding long-term effects of kinase activity on transporter function, 24 h incubation with 10 µM epinephrine has been demonstrated to down-regulate hOCT1 mRNA-expression via cAMP formation in primary human hepatocytes ( Mayati et al, 2017a ). These results confirm what was observed for rapid regulation of hOCT1 under stimulation of PKA activity ( Ciarimboli et al, 2004 ), showing that this regulation axis has similar short- and long-term effects on hOCT1 function.…”

Section: Long-term Regulation Of Oct1mentioning

confidence: 99%

Regulation Mechanisms of Expression and Function of Organic Cation Transporter 1

Ciarimboli¹

2021

Front. Pharmacol.

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The organic cation transporter 1 (OCT1) belongs together with OCT2 and OCT3 to the solute carrier family 22 (SLC22). OCTs are involved in the movement of organic cations through the plasma membrane. In humans, OCT1 is mainly expressed in the sinusoidal membrane of hepatocytes, while in rodents, OCT1 is strongly represented also in the basolateral membrane of renal proximal tubule cells. Considering that organic cations of endogenous origin are important neurotransmitters and that those of exogenous origin are important drugs, these transporters have significant physiological and pharmacological implications. Because of the high expression of OCTs in excretory organs, their activity has the potential to significantly impact not only local but also systemic concentration of their substrates. Even though many aspects governing OCT function, interaction with substrates, and pharmacological role have been extensively investigated, less is known about regulation of OCTs. Possible mechanisms of regulation include genetic and epigenetic modifications, rapid regulation processes induced by kinases, regulation caused by protein–protein interaction, and long-term regulation induced by specific metabolic and pathological situations. In this mini-review, the known regulatory processes of OCT1 expression and function obtained from in vitro and in vivo studies are summarized. Further research should be addressed to integrate this knowledge to known aspects of OCT1 physiology and pharmacology.

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β2-adrenergic receptor-mediated in vitro regulation of human hepatic drug transporter expression by epinephrine

Cited by 8 publications

References 64 publications

mRNA Expression and Activity of Nucleoside Transporters in Human Hepatoma HepaRG Cells

mRNA Expression and Activity of Nucleoside Transporters in Human Hepatoma HepaRG Cells

Biphasic modulation of cAMP levels by the contraceptive nomegestrol acetate. Impact on P-glycoprotein expression and activity in hepatic cells

Regulation Mechanisms of Expression and Function of Organic Cation Transporter 1

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