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  • Steady state mRNA levels of CYP A isoforms were not

    2019-07-13

    Steady-state mRNA levels of CYP3A isoforms were not changed during liver insufficiency. Suppression of these isoforms was observed only at the protein and activity levels, suggesting a nongenomic mechanism of CYP3A isoform downregulation during liver insufficiency. Nonetheless, transcriptional activation of CYP3A isoforms was observed after induced dysfunction of the serotonergic system during normal liver function. Moreover, the activity of these isoforms was also increased, while the protein level of CYP3A2 was not changed, suggesting that posttranslational stabilization of this isoform is also under control of the serotonergic system. Dysfunction of the serotonergic system during liver insufficiency led to suppression of CYP3A isoforms at the gene, protein and activity levels by a mechanism based on posttranscriptional and posttranslational processes. The altered immune profile suggested the key role of the glucocorticoid (GC) receptor in this mechanism. The glucocorticoid receptor crucially regulates the transcription of mediators of the immune system by both suppressing (IL-1β, TNFα and IL-6) and stimulating (IL-4 and TGF-β1, although the latter is controversial) the production of a large number of proinflammatory or anti-inflammatory cytokines (Elenkov, 2004; Franchimont, 2004). Moreover, the GR participates in the PXR-mediated induction of the A939572 of CYP3A isoforms through a unique integrative mechanism (Huss and Kasper, 2000; Pascussi et al., 2008; De Martin et al., 2014). In our study, the level of the PXR protein, a confirmed mediator of CYP3A isoform expression, was increased after serotonergic system dysfunction only during normal liver function. Dysfunction of serotonergic system during liver insufficiency results in a decreased GR protein level and increased STAT6 and ERK1/2 protein levels in the nuclear fraction of the liver, suggesting the creation of conditions for alterations in GR phosphorylation that are important for subcellular localization of the GR protein. The specific site of GR phosphorylation is currently unknown and will be examined in a future study. Consistent with this interpretation, previous studies have shown that GR is a phosphoprotein containing numerous phosphorylation sites, including sites for pERK, p38 MAPK, PKC, and PKA, and alterations in GR phosphorylation status affect its subcellular localization and nuclear-cytoplasmic shuttling (Jans and Hübner, 1996; Ismaili and Garabedian, 2004). Moreover, the transcriptional interference between the GR-mediated and IL-4-mediated signal transduction pathways is based on the mutual transcriptional repressive activities of GR and STAT6 in T lymphocytes, whereas increased STAT6 activity is effectively blocked by an MEK/ERK inhibitor (Biola et al., 2000; Shaul and Segar, 2007; So et al., 2007).
    Author contributions
    Acknowledgments This work was supported by the Polish National Science Center grant SONATA [2012/07/D/NZ4/00814] and by the Ministry of Sciences and Higher Education [556/MOB/2009/0].
    Introduction Oral contraceptives (OCs) are one of the most widely used drugs by women. Therefore, the potential for interaction with other drugs is high and often has clinically significant consequences [1]. Most OCs contain both a synthetic estrogen (ethinylestradiol) and a synthetic progesterone (progestin) such as norethisterone, norgestrel, levonorgestrel, desogestrel, gestodene, or medroxyprogesterone. Ethinylestradiol undergoes hydroxylation at the 2-position and oxidation of the 17α-acetylenic bond, which is catalyzed by cytochrome P450 3A (CYP3A) [2], [3]. Progestins can also undergo oxidation at the 17α-acetylenic bond by CYP3A. A number of drugs and dietary components are known to inhibit or induce the catalytic activity of CYP3A [1], [4], [5]. There have been many studies on the induction and inhibition of CYP3A, which is involved in the metabolism of OCs, by other drugs [6], [7], [8], [9]. The induction of CYP3A may increase the clearance of OCs, decreasing their clinical efficacy [10]. On the other hand, few studies have assessed the influence of OCs on the metabolism and pharmacokinetics of other drugs [11], [12], [13]. Acetylenic steroids, such as ethinylestradiol and levonorgestrel, are mechanism-based inhibitors of CYP3A mediated-metabolism in in vitro studies [14].