Protective effect of heme oxygenase induction in ethinylestradiol‐induced cholestasis

• DOI: 10.1111/jcmm.12401
• Publication Date: 2015-02-16T08:09:49Z
• Authors: Lucie Muchova; Katerina Vanova; Jakub Suk; Stanislav Micuda; Eva Dolezelova; Leos Fuksa; Dalibor Cerny; Hassan Farghali; Miroslava Zelenkova; Martin Lenicek; Ronald J. Wong; Hendrik J. Vreman; Libor Vitek
• Keywords: HMOX1; Ethinylestradiol

Estrogen-induced cholestasis is characterized by impaired hepatic uptake and biliary bile acids secretion because of changes in hepatocyte transporter expression. The induction heme oxygenase-1 (HMOX1), the inducible isozyme catabolism, mediated via Bach1/Nrf2 pathway, protects livers from toxic, oxidative inflammatory insults. However, its role remains unknown. Here, we investigated effects HMOX1 on ethinylestradiol-induced possible underlying mechanisms. Wistar rats were given ethinylestradiol (5 mg/kg s.c.) for 5 days. was induced (15 μmol/kg i.p.) 24 hrs prior to ethinylestradiol. Serum cholestatic markers, renal membrane expression, urinary excretion quantified. Ethinylestradiol significantly increased markers (P ≤ 0.01), decreased acid (39%, P = down-regulated transporters (Ntcp/Oatp1b2/Oatp1a4/Mrp2, 0.05), up-regulated Mrp3 (348%, 0.05). Heme pre-treatment normalized (167%, 0.05) Moreover, expression control (319%, ethinylestradiol-treated (512%, In primary rat hepatocytes, Nrf2 silencing completely abolished heme-induced Additionally, clearance up-regulation (Mrp2/Mrp4) or down-regulation (Mrp3) We conclude that increases subsequently stimulating flow cholestasis. Also, stimulates a Nrf2-dependent mechanism. Bile transported plasma are highly cleared into urine, resulting normal levels. Thus, may be potential therapeutic strategy treatment