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  • Introduction Epinephrine is an endocrine hormone mainly prod

    2023-01-21

    Introduction Epinephrine is an endocrine hormone mainly produced by adrenal medulla in response to stress (Tank and Lee Wong, 2015). This catecholamine exerts various major physiological effects, concerning notably the cardiovascular system, the respiratory system and the endocrine system, through acting as a potent agonist of α and/or β adrenergic receptors (ADRs) (Strosberg, 1993). Hepatocytes, that display notable expression of α1- and β2-ADRs (Aggerbeck et al., 1983), are recognized as known cellular targets of epinephrine (Morgan et al., 1983). In this context, the hepatic drug detoxifying system is likely one of the various hepatic metabolic ways affected by the catecholamine. Indeed, epinephrine has been shown to modulate expression of several drug-metabolizing cytochromes P-450 (CYPs) in rat hepatocytes (Daskalopoulos et al., 2012, Iber et al., 2001). It also targets CYP levels in human hepatic cells, notably those of CYP3A4 and CYP1A2 that are reduced in both primary human hepatocytes and human high-differentiated hepatoma HepaRG Cy5 carboxylic acid (non-sulfonated) receptor exposed to epinephrine, which has been suggested to be linked to a β2-adrenergic pro-inflammatory effect exerted by the catecholamine via interleukin (IL)-6 induction (Aninat et al., 2008). Besides drug metabolizing enzymes, drug transporters are now recognized as major actors of the hepatic drug detoxification system (Funk, 2008, Lecureur et al., 2000, Li et al., 2009). They are implicated in uptake of drugs into hepatocytes at their sinusoidal pole (Fahrmayr et al., 2010) and also in biliary secretion of drugs or drug metabolites at the canalicular pole of hepatocytes (Pfeifer et al., 2014), acting thus in a coordinate manner with drug metabolizing enzymes for permitting hepatobiliary elimination of xenobiotics (Stieger and Hagenbuch, 2016). Transporter expression is also coordinately regulated with that of drug metabolizing enzymes such as CYPs (Eloranta et al., 2005, Fardel et al., 2001). Activation of drug sensing receptors like aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR) and constitutive androstane receptor (CAR) has thus been demonstrated to control hepatic expression of CYP2B6, CYP3A4 and drug transporters like P-glycoprotein, encoded by multidrug resistance gene 1 (MDR1) gene (ABCB1), multidrug resistance-associated protein (MRP) 2 (ABCC2), MRP3 (ABCC3), MRP4 (ABCC4) and breast cancer resistance protein (BCRP/ABCG2) (Amacher, 2016, Klaassen and Aleksunes, 2010, Kohle and Bock, 2009). Inflammatory cytokines such as IL-1β and IL-6 also modulate in a similar way hepatic levels of CYPs and drug transporters (Fardel and Le Vee, 2009, Morgan et al., 2008, Petrovic et al., 2007). Whether epinephrine, regulating hepatic CYP expression as mentioned above (Aninat et al., 2008), may also act on that of hepatic drug transporters remains however unknown. The present study was therefore designed to analyze the effects of epinephrine on functional expression of main hepatic solute carrier (SLC) and ATP-binding cassette (ABC) transporters in human hepatocytes. Our data indicate that epinephrine treatment down-regulates expression of several sinusoidal uptake and canalicular hepatic transporters, through activation of a β2-ADR/adenylate cyclase/cAMP pathway.
    Materials and methods
    Results
    Discussion The present study demonstrates that epinephrine can regulate in vitro expression of human hepatic drug transporters. Associated to the fact that this catecholamine also impairs levels of hepatic CYP expression (Aninat et al., 2008), these data therefore support the idea that epinephrine likely acts as a physiological regulator of the hepatic drug detoxifying machinery. The catecholamine may consequently be added to the growing list of effectors that coordinately regulate drug metabolizing enzymes and drug transporters (Kohle and Bock, 2009). Most of transporters regulated by epinephrine were down-regulated at the mRNA level in human hepatocytes. This was notably the case for the sinusoidal influx transporters NTCP, OCT1, OATP1B1, OATP2B1, OAT2 and OAT7 and for the efflux transporters MRP2, MRP3 and BSEP, whereas, by contrast, MDR1 mRNA expression was induced and that of BCRP remained unchanged. Such regulations were also found in HepaRG cells, with minor variations, i.e., MRP2 and MDR1 mRNA levels were only transiently down-regulated and up-regulated, respectively, in HepaRG cells. Such a similar transporter regulation in response to epinephrine occurring in both HepaRG cells and human hepatocytes fully supports the now well-established relevance of HepaRG cells as surrogates for human hepatocytes (Antherieu et al., 2012). OATP1B3 mRNA expression was however markedly differently regulated in human hepatocytes versus HepaRG cells; this influx transporter was thus transiently repressed in human hepatocytes exposed to epinephrine, whereas it was induced in HepaRG cells. A similar discrepancy for OATP1B3 regulation between hepatocytes and HepaRG cells has already been reported in response to the protein kinase C activator phorbol myristate acetate (Mayati et al., 2015) or to all-trans retinoic acid (Le Vee et al., 2013a). This may be due to the very low constitutive expression of OATP1B3 in HepaRG cells (Le Vee et al., 2013b). Interestingly, epinephrine-mediated regulations of transporter mRNA levels in HepaRG cells were associated with parallel regulations of transporter protein levels, notably for OATP2B1, MDR1/P-glycoprotein and MRP3, whereas protein expression of BCRP remained unchanged, as for its mRNA levels. MRP2 protein expression was also not obviously altered by epinephrine, which likely reflects the fact that MRP2 mRNA repression by the catecholamine was only transient and rather slight. In parallel, epinephrine reduced activity of NTCP, OCT1 and OATP, thus indicating that the down-regulation of these transporters has functional consequences.