Protective effect of heme oxygenase induction in ethinylestradiol‐induced cholestasis

Journal of Cellular and Molecular Medicine

Lucie Muchova¹  Katerina Vanova¹  Jakub Suk¹  Stanislav Micuda³  Eva Dolezelova³  Leos Fuksa³  Dalibor Cerny⁴  Hassan Farghali⁴  Miroslava Zelenkova¹  Martin Lenicek¹  Ronald J. Wong²  Hendrik J. Vreman² 

[1] Institute of Medical Biochemistry and Laboratory Diagnostics, 1^st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic;Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA;Department of Pharmacology, Charles University in Hradec Kralove, Prague, Czech Republic;Department of Pharmacology, 1^st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic

关键词: 17α‐ ethinylestradiol;    heme;    nuclear factor erythroid‐2‐related factor‐2;    bile acids;    multidrug resistance‐associated protein 3;   

DOI  :  10.1111/jcmm.12401

来源: Wiley

【 摘 要 】

Abstract

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

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© 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

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