Dioscin protects against ANIT–induced cholestasis via regulating Oatps, Mrp2 and Bsep expression in rats

Zhang, Aijie; Jia, Yongming; Xu, Qinghan; Wang, Changyuan; Liu, Qi; Meng, Qiang; Peng, Jinyong; Sun, Huijun; Sun, Pengyuan; Huo, Xiaokui; Liu, Kexin

doi:10.1016/j.taap.2016.06.019

Cited by 35 publications

(29 citation statements)

References 40 publications

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“…Progressive familial intrahepatic cholestasis type 1 or 2 (PFIC 1/2) and Dubin-Johnson syndrome are such diseases, and are due to a deficiency of BSEP and MRP2, respectively. 17,18) In our study, we also verified the alteration of the expression of BSEP and MRP2 after treatment with INH in HepG2 cells. The down-regulation of BSEP and MRP2 was observed after treatment with 100 mM INH, which was associated with a decrease in cell viability.…”

Section: Discussionsupporting

confidence: 72%

Dysregulation of BSEP and MRP2 May Play an Important Role in Isoniazid-Induced Liver Injury <i>via</i> the SIRT1/FXR Pathway in Rats and HepG2 Cells

Zhang

et al. 2018

Biological & Pharmaceutical Bulletin

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To explore the role of the abnormal expression of the bile salt export pump (BSEP) and multidrug resistance protein 2 (MRP2) in isoniazid (INH)-induced liver injury, we assessed the liver injury induced by INH in rats and HepG2 cells in vitro. The regulatory pathways via Sirtuin 1 (SIRT1) and farnesoid X receptor (FXR) were also determined. Rat liver injury was assessed by histopathological and biochemical analysis and HepG2 cytotoxicity was assessed by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test. The levels of protein were determined by Western blot. The results indicated that INH could induce hepatotoxicity in vivo and in vitro in a dose dependent manner. The liver index and serum biochemical analysis, especially the levels of total bile acids (TBA), total bilirubin (TBIL), and direct bilirubin (DBIL), were significantly increased in rats. The INH hepatotoxicity was severe in the high dose group, and occurred alongside the down-regulation of BSEP and MRP2 in vivo and in vitro, leading to the accumulation of toxic substrates in the hepatocytes. The SIRT1/FXR pathway was identified as being important for the down-regulation of transporters. In summary, our study indicated that the down-regulation of BSEP and MRP2 represents one mechanism of INH-induced liver injury and the down-regulation of SIRT1/FXR may be a key regulator. This will inform the development of novel therapies and enable the prevention of INH-induced liver injury.

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Section: Discussionsupporting

confidence: 72%

Dysregulation of BSEP and MRP2 May Play an Important Role in Isoniazid-Induced Liver Injury <i>via</i> the SIRT1/FXR Pathway in Rats and HepG2 Cells

Zhang

et al. 2018

Biological & Pharmaceutical Bulletin

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“…All samples were initially snap frozen, and subsequently stored at 280°C. Liver viability was assessed by monitoring portal perfusion pressure (,15 cm H 2 O), gross morphology, bile flow (.2 ml/min) (Zhang et al, 2016), and lactate dehydrogenase (LDH) levels in the outflow perfusate measured by a Pierce LDH Cytotoxicity Assay Kit (Thermo Fisher Scientific, Waltham, MA) per the manufacturer's instructions. As a positive control for the LDH assay, one WT rat liver was perfused with 1% Triton X-100, which resulted in immediate liver toxicity based on gross morphology and major LDH release in outflow perfusate.…”

Section: Methodsmentioning

confidence: 99%

Altered Hepatobiliary Disposition of Tolvaptan and Selected Tolvaptan Metabolites in a Rodent Model of Polycystic Kidney Disease

et al. 2018

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Tolvaptan, a vasopressin V 2 -receptor antagonist, has demonstrated efficacy in slowing kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD). In the pivotal clinical trial, the incidence of elevated liver enzymes was higher in patients receiving tolvaptan compared with placebo. Adjudication by a panel of expert hepatologists concluded a causal link of tolvaptan to liver injury in patients with ADPKD. An ex situ isolated perfused liver (IPL) study of tolvaptan disposition was undertaken in a rodent model of ADPKD, the polycystic kidney (PCK) rat (n = 5), and compared with wild-type (WT) Sprague-Dawley rats (n = 6). Livers were perfused with tolvaptan, followed by a tolvaptan-free washout phase. Total recovery (mean 6 S.D. percentage of dose; PCK vs. WT) of tolvaptan and two metabolites, DM-4103 and DM-4107, quantified by liquid chromatography-tandem mass spectroscopy, was 58.14% 6 24.72% vs. 43.40% 6 18.11% in liver, 20.10% 6 9.15% vs. 21.17% 6 12.51% in outflow perfusate, and 0.08% 6 0.01% vs. 0.39% 6 0.32% in bile. DM-4103 recovery (mean 6 S.D. percentage of dose) was decreased in PCK vs. WT bile (<0.01% 6 <0.01% vs. 0.02% 6 0.01%; P = 0.0037), and DM-4107 recovery was increased in PCK vs. WT outflow perfusate (1.60% 6 0.57% vs. 0.43% 6 0.29%; P = 0.0017). A pharmacokinetic compartmental model assuming first-order processes was developed to describe the rate vs. time profiles of tolvaptan and DM-4103 + DM-4107 in rat IPLs. The model-derived estimate of tolvaptan's biliary clearance was significantly decreased in PCK compared with WT IPLs. The model predicted greater hepatocellular concentrations of tolvaptan and DM-4103 + DM-4107 in PCK compared with WT IPLs. Increased hepatocellular exposure to tolvaptan and metabolites may contribute to the hepatotoxicity in patients with ADPKD treated with tolvaptan.

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“…Together with the function of the bile salt export pump (in humans, BSEP; in rodents, Bsep), promoting the combined bile salts with renal excretion when cholestasis. [28][29][30] Mrp3 exists in the liver cell side of the base film, weak expression in normal liver, but significant expression when cholestasis. It is the major transporter to absorb the bile salts from bile, and then excretes to portal vein circulation when cholestasis.…”

Section: Discussionmentioning

confidence: 99%

Pinelliae Rhizoma Praeparatum Involved in the Regulation of Bile Acids Metabolism in Hepatic Injury

Guo

Zhang

Liu

et al. 2018

Biological & Pharmaceutical Bulletin

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Pinelliae Rhizoma Praeparatum (PRP) as traditional Chinese medicine had been used for hepatic diseases in combinative forms. However, the effect of PRP was not clear when used alone. So to explore the hepatoprotective/hepatotoxin of PRP is necessary. The activities of PRP were investigated in acetaminophen-induced hepatic injury mice. Liver function markers, hepatic oxidative stress markers were evaluated. Bile acids metabolic transports and nuclear factor erythroid 2-related factor 2 (Nrf2) were detected. As a drug for the treatment of liver diseases, PRP slightly restored the parameters towards normal in model mice only in low dosage, and also had no antioxidant activity and regulate Nrf2. Cholestasis was significantly elevated in model mice when pretreatment with routine or high dosage of PRP, but had no effect on normal mice. Bile salt export pump (Bsep) and multidrug resistance-associated protein 2 (Mrp2) in model mice were markedly increased when pretreatment with low dose PRP, but significantly decreased when pretreatment in routine or high dosage. Mrp3 was significantly induced in model mice after pretreatment of PRP. But the adjustment effect to bile acids transporters by PRP was not significant in normal mice. These results reveal that PRP has the different effects on bile acids transporter in hepatic injury mice, and therefore, the dosage of PRP need to be paid attention to when it is used in clinical hepatic injury.

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Dioscin protects against ANIT–induced cholestasis via regulating Oatps, Mrp2 and Bsep expression in rats

Cited by 35 publications

References 40 publications

Dysregulation of BSEP and MRP2 May Play an Important Role in Isoniazid-Induced Liver Injury <i>via</i> the SIRT1/FXR Pathway in Rats and HepG2 Cells

Dysregulation of BSEP and MRP2 May Play an Important Role in Isoniazid-Induced Liver Injury <i>via</i> the SIRT1/FXR Pathway in Rats and HepG2 Cells

Altered Hepatobiliary Disposition of Tolvaptan and Selected Tolvaptan Metabolites in a Rodent Model of Polycystic Kidney Disease

Pinelliae Rhizoma Praeparatum Involved in the Regulation of Bile Acids Metabolism in Hepatic Injury

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