Effect of Yin–Zhi–Huang on up-regulation of Oatp2, Ntcp, and Mrp2 proteins in estrogen-induced rat cholestasis

Abstract Context: Yin–Zhi–Huang (YZH), a prescription of traditional Chinese medicine, is widely used to treat neonatal jaundice or cholestasis. Objective: This study investigates the regulatory effect of YZH on the localization and expression of organic anion transporting polypeptides 2 (Oatp2), Na+-taurocholate co-transporting polypeptide (Ntcp), multidrug-resistance-associated protein 2 (Mrp2), and bile salt export pump (Bsep) in estrogen-induced cholestasis rats. Material and methods: Cholestasis model rats were induced via subcutaneous injection of estradiol benzoate (EB, 5 mg/kg/d) for 5 d. Other EB-induced rats were treated with saline (2 ml) or YZH (1.5 g/kg, two times a day) for 7, 14, and 21 d. The biochemical and pathologic examinations were performed. Moreover, the localization and expression of Oatp2, Ntcp, Mrp2, and Bsep were determined by immunohistochemisty and Western blotting, respectively. Results: YZH treatment could significantly decrease the serum total bile acids (TBA) (4.9 ± 0.6–2.8 ± 0.8) and direct bilirubin (DBIL) (2.6 ± 0.7–1.0 ± 0.1) levels, improve the histological disorganization, and, respectively, increase the expression of Oatp2 and Ntcp by 46% and 28% compared with saline-treated (p < 0.05) rats at 14 d. The expression of Mrp2 increased by 45% was observed in YZH treated compared with saline-treated (p < 0.05) rats at 7 d. However, there was a little change in the expression of Bsep (p > 0.05) after YZH treatment for 7, 14, and 21 d. Discussion and conclusion: In conclusion, the therapeutic effect of YZH to cholestasis could be attributed to the regulation of Oatp2, Ntcp, Mrp2, and Bsep.

[1]  T. Horie,et al.  LPS-induced dissociation of multidrug resistance-associated protein 2 (Mrp2) and radixin is associated with Mrp2 selective internalization in rats. , 2011, Biochemical pharmacology.

[2]  M. Niemi,et al.  Impact of OATP transporters on pharmacokinetics , 2009, British journal of pharmacology.

[3]  K. Setchell,et al.  3α-6α-Dihydroxy-7α-fluoro-5β-cholanoate (UPF-680), physicochemical and physiological properties of a new fluorinated bile acid that prevents 17α-ethynyl-estradiol-induced cholestasis in rats , 2006 .

[4]  Rick Moore,et al.  Estrogen Receptor α Mediates 17α-Ethynylestradiol Causing Hepatotoxicity* , 2006, Journal of Biological Chemistry.

[5]  D. Moore,et al.  A traditional herbal medicine enhances bilirubin clearance by activating the nuclear receptor CAR. , 2004, The Journal of clinical investigation.

[6]  M. Trauner,et al.  Molecular aspects of bile formation and cholestasis. , 2003, Trends in molecular medicine.

[7]  Y. Moriyama,et al.  Co‐expression of vesicular glutamate transporters (VGLUT1 and VGLUT2) and their association with synaptic‐like microvesicles in rat pinealocytes , 2003, Journal of neurochemistry.

[8]  P. Meier,et al.  Bile salt transporters. , 2002, Annual review of physiology.

[9]  L. Wu,et al.  [Study on hepatic-protective effect of "yinzhihuang" granula]. , 2001, Zhong yao cai = Zhongyaocai = Journal of Chinese medicinal materials.

[10]  Y. Sugiyama,et al.  Characterization of bile acid transport mediated by multidrug resistance associated protein 2 and bile salt export pump. , 2001, Biochimica et biophysica acta.

[11]  K. Zatloukal,et al.  Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases , 2001, Hepatology.

[12]  R. Wennberg,et al.  Induction of hepatic bilirubin-metabolizing enzymes by the traditional Chinese medicine yin zhi huang. , 1991, Developmental pharmacology and therapeutics.