Protective effect of heme oxygenase induction in ethinylestradiol-induced cholestasis

被引:26
作者
Muchova, Lucie [1 ]
Vanova, Katerina [1 ]
Suk, Jakub [1 ]
Micuda, Stanislav [2 ]
Dolezelova, Eva [2 ,3 ]
Fuksa, Leos [2 ]
Cerny, Dalibor [4 ]
Farghali, Hassan [4 ]
Zelenkova, Miroslava [1 ]
Lenicek, Martin [1 ]
Wong, Ronald J. [5 ]
Vreman, Hendrik J. [5 ]
Vitek, Libor [1 ,6 ,7 ]
机构
[1] Charles Univ Prague, Fac Med 1, Inst Med Biochem & Lab Diagnost, Prague 12801 2, Czech Republic
[2] Charles Univ Hradec Kralove, Dept Pharmacol, Prague, Czech Republic
[3] Charles Univ Prague, Fac Pharm, Dept Biol & Med Sci, Prague 12801 2, Czech Republic
[4] Charles Univ Prague, Fac Med 1, Dept Pharmacol, Prague 12801 2, Czech Republic
[5] Stanford Univ, Dept Pediat, Sch Med, Stanford, CA 94305 USA
[6] Charles Univ Prague, Fac Med 1, Dept Internal Med 4, Prague 12801 2, Czech Republic
[7] Gen Fac Hosp Prague, Prague, Czech Republic
关键词
17-ethinylestradiol; heme; nuclear factor erythroid-2-related factor-2; bile acids; multidrug resistance-associated protein 3; ESTROGEN-INDUCED CHOLESTASIS; ORGANIC ANION TRANSPORTERS; BILE-SALT TRANSPORTERS; CARBON-MONOXIDE; RAT-LIVER; OXIDATIVE STRESS; BILIRUBIN LEVELS; REGULATOR; SYSTEM; PATHOGENESIS;
D O I
10.1111/jcmm.12401
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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 (5mg/kg s.c.) for 5days. HMOX1 was induced by heme (15mol/kg i.p.) 24hrs 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 (P0.01), decreased biliary bile acid excretion (39%, P=0.01), down-regulated hepatocyte transporters (Ntcp/Oatp1b2/Oatp1a4/Mrp2, P0.05), and up-regulated Mrp3 (348%, P0.05). Heme pre-treatment normalized cholestatic markers, increased biliary bile acid excretion (167%, P0.05) and up-regulated hepatocyte transporter expression. Moreover, heme induced Mrp3 expression in control (319%, P0.05) and ethinylestradiol-treated rats (512%, P0.05). 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 (P0.05). 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.
引用
收藏
页码:924 / 933
页数:10
相关论文
共 48 条
[41]   ENZYMATIC CONVERSION OF HEME TO BILIRUBIN BY MICROSOMAL HEME OXYGENASE [J].
TENHUNEN, R ;
MARVER, HS ;
SCHMID, R .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1968, 61 (02) :748-&
[42]   Bile salt transporters: Molecular characterization, function, and regulation [J].
Trauner, M ;
Boyer, JL .
PHYSIOLOGICAL REVIEWS, 2003, 83 (02) :633-671
[43]   Protective effects of inhaled carbon monoxide in endotoxin-induced cholestasis is dependent on its kinetics [J].
Vanova, K. ;
Suk, J. ;
Petr, T. ;
Cerny, D. ;
Slanar, O. ;
Vreman, H. J. ;
Wong, R. J. ;
Zima, T. ;
Vitek, L. ;
Muchova, L. .
BIOCHIMIE, 2014, 97 :173-180
[44]   CARBON-MONOXIDE - A PUTATIVE NEURAL MESSENGER [J].
VERMA, A ;
HIRSCH, DJ ;
GLATT, CE ;
RONNETT, GV ;
SNYDER, SH .
SCIENCE, 1993, 259 (5093) :381-384
[45]   The inverse association of elevated serum bilirubin levels with subclinical carotid atherosclerosis [J].
Vitek, Libor ;
Novotny, Ladislav ;
Sperl, Michal ;
Holaj, Robert ;
Spacil, Jiri .
CEREBROVASCULAR DISEASES, 2006, 21 (5-6) :408-414
[46]   HEME OXYGENASE ACTIVITY AS MEASURED BY CARBON-MONOXIDE PRODUCTION [J].
VREMAN, HJ ;
STEVENSON, DK .
ANALYTICAL BIOCHEMISTRY, 1988, 168 (01) :31-38
[47]   Heme oxygenase: A novel target for the modulation of the inflammatory response [J].
Willis, D ;
Moore, AR ;
Frederick, R ;
Willoughby, DA .
NATURE MEDICINE, 1996, 2 (01) :87-90
[48]   Hemin Exerts Multiple Protective Mechanisms and Attenuates Dextran Sulfate Sodium-induced Colitis [J].
Zhong, Wenwei ;
Xia, Zhenwei ;
Hinrichs, David ;
Rosenbaum, James T. ;
Wegmann, Keith W. ;
Meyrowitz, Jeffery ;
Zhang, Zili .
JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION, 2010, 50 (02) :132-139