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

Biphasic modulation of cAMP levels by the contraceptive nomegestrol acetate. Impact on P-glycoprotein expression and activity in hepatic cells. Biochem Pharmacol. 2018 Apr 20;: Authors: Tocchetti GN, Domínguez CJ, Zecchinati F, Arana MR, Ruiz ML, Villanueva SSM, Weiss J, Mottino AD, Rigalli JP Abstract 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 identifie...
Source: Biochemical Pharmacology - Category: Drugs & Pharmacology Authors: Tags: Biochem Pharmacol Source Type: research