Modulation of expression and activity of p-glycoprotein by the progestin Nomegestrol Acetate in HEPG2 cells. involvement of membrane progesterone receptor.

RIGALLI JUAN PABLO; ARANA MAITE ROCIO; WEISS JOHANNA; TOCCHETTI GUILLERMO NICOLÁS; ZECCHINATI FELIPE; VILLANUEVA SILVINA STELLA MARIS; DOMINGUEZ CAMILA JULIANA; RUIZ MARÍA LAURA; MOTTINO ALDO DOMINGO

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

Introduction: Nomegestrol acetate (NMGA) is a synthetic progestin increasingly used for oral contraception. Due to long-term NMGA therapy, concurrent use with other drugs is highly feasible. P-glycoprotein (P-gp; ABCB1) is a key player in drug excretion. Alterations in its activity represent a common cause of drug-drug interactions (DDI). Up to date, there is scarce data about modulation of ABC transporters by NMGA.Aims: (1) to evaluate the modulation of P-gp expression and activity by NMGA (0.5 ? 500 nM) in the human he-patic cell line HepG2 and (2) to identify the underlying mechanisms.Materials & methods: Protein expression was assessed by western blot and corresponding mRNA by qRT-PCR. mRNA stability was evaluated using actinomycin D. Pgp activity was evaluated by quantifying the intracellular accumulation of the model substrate calcein by flow cytometry. Progesterone receptor (PR) and Gi protein were inhibited using RU486 and pertussis toxin, respectively. Membrane progester-one receptor a (mPRa) was knocked down using siRNA. Results: NMGA (5, 50 and 500 nM; 48 h) increased P-gp protein expression (+83%, +77% and +93%, p