Role of MRP2 and GSH in intrahepatic cycling of toxins

Dietrich, Christoph G.

doi:10.1016/s0300-483x(01)00459-0

Cited by 157 publications

(112 citation statements)

References 21 publications

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“…However, sweroside attenuated ANIT-induced changes in Mrp2, Ost-β, Mdr1, Ntcp, Oatp1a1, and Oatp1b2 expression, thereby restoring the disruption of bile acid profile. Mrp2 is an efflux transporter that mediates the secretion of toxic endogenous and exogenous compounds in the form of amphiphilic anionic conjugates via an ATP-dependent mechanism [37,38] . Sweroside treatment enhanced Mrp2 expression, which may have contributed to the accelerated secretion of hepatic bile acids.…”

Section: Discussionmentioning

confidence: 99%

Sweroside ameliorates α-naphthylisothiocyanate-induced cholestatic liver injury in mice by regulating bile acids and suppressing pro-inflammatory responses

Yang

Gong

et al. 2016

Acta Pharmacol Sin

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Aim: Sweroside is an iridoid glycoside with diverse biological activities. In the present study we investigated the effects of sweroside on α-naphthylisothiocyanate (ANIT)-induced cholestatic liver injury in mice. Methods: Mice received sweroside (120 mg·kg -1 ·d -1 , ig) or a positive control INT-747 (12 mg·kg -1 ·d -1 , ig) for 5 d, and ANIT (75 mg/kg, ig) was administered on d 3. The mice were euthanized on d 5, and serum biochemical markers, hepatic bile acids and histological changes were analyzed. Hepatic expression of genes related to pro-inflammatory mediators and bile acid metabolism was also assessed. Primary mouse hepatocytes were exposed to a reconstituted mixture of hepatic bile acids, which were markedly elevated in the ANIT-treated mice, and the cell viability and expression of genes related to pro-inflammatory mediators were examined. Results: Administration of sweroside or INT-747 effectively ameliorated ANIT-induced cholestatic liver injury in mice, as evidenced by significantly reduced serum biochemical markers and attenuated pathological changes in liver tissues. Furthermore, administration of sweroside or INT-747 significantly decreased ANIT-induced elevation of individual hepatic bile acids, such as β-MCA, CA, and TCA, which were related to its effects on the expression of genes responsible for bile acid synthesis and transport as well as pro-inflammatory responses. Treatment of mouse hepatocytes with the reconstituted bile acid mixture induced significant pro-inflammatory responses without affecting the cell viability. Conclusion: Sweroside attenuates ANIT-induced cholestatic liver injury in mice by restoring bile acid synthesis and transport to their normal levels, as well as suppressing pro-inflammatory responses.

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Section: Discussionmentioning

confidence: 99%

Sweroside ameliorates α-naphthylisothiocyanate-induced cholestatic liver injury in mice by regulating bile acids and suppressing pro-inflammatory responses

Yang

Gong

et al. 2016

Acta Pharmacol Sin

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“…Thus, we used ANIT in rats to model intrahepatic cholestasis and then sought to determine whether resveratrol plays a protective and/or adaptive role in this type of liver injury [20,21] . Markers for liver injury and cholestasis, such as serum ALT, AST, ALP, GGT, bile acids and bilirubin, were increased 24 h (data not shown) after ANIT administration and peaked at 48 h (Table 2).…”

Section: Wwwchinapharcom Wang T Et Almentioning

confidence: 99%

“…Oxidative injury likely plays a large role in ANIT-induced biliary epithelial injury, possibly as a result of one or more sulfhydryl-reactive intermediates created by repeated rounds of secretion and reuptake of the glutathione conjugate [20,24] . Mitochondria are an important source of reactive oxygen species, particularly after cholestasis, when their antioxidant properties are exhausted [25] .…”

Section: Wwwchinapharcom Wang T Et Almentioning

confidence: 99%

“…ANIT is conjugated with GSH in hepatocytes and transported into the bile by multidrug resistance-associated protein (Mrp) 2 (Abcc2), the canalicular efflux transporter. The ANIT-GSH conjugate dissociates upon crossing the canalicular membrane, yielding free GSH and ANIT in the bile [20,33] . In this study, the biliary secretions of GSH were extensively increased by resveratrol, which may contribute to the secretion of ANIT.…”

Section: Wwwchinapharcom Wang T Et Almentioning

confidence: 99%

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Resveratrol effectively attenuates α-naphthyl-isothiocyanate-induced acute cholestasis and liver injury through choleretic and anti-inflammatory mechanisms

et al. 2014

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Aim: α-Naphthylisothiocyanate (ANIT) is a well-characterized cholestatic agent for rats. The aim of this study was to examine whether resveratrol could attenuate ANIT-induced acute cholestasis and liver injury in rats. Methods: SD rats were treated with resveratrol (15 or 30 mg/kg, ip) or a positive control drug ursodeoxycholic acid (100 mg/kg, po) for 5 consecutive days followed by a single dose of ANIT (60 mg/kg, po). Bile flow, and serum biochemical markers and bile constituents were measured 48 h after ANIT administration. Hepatic levels of oxidative repair enzymes (glutathione peroxidase, catalase and MnSOD), myeloperoxidase activity, TNF-α, IL-6, and ATP content, as well as the expression of liver transporter genes and proteins were assayed. Results: ANIT exposure resulted in serious cholestasis and liver injury, as shown by marked neutrophil infiltration in liver, dramatically increased serum levels of ALT, AST, GGT, ALP, TBA, TBIL, IBIL, and DBIL, and significantly decreased bile excretion and biliary output of GSH and HCO 3 -. ANIT significantly increased TNF-α and IL-6 release and myeloperoxidase activity, decreased mitochondrial biogenesis in liver, but had little effect on hepatic oxidative repair enzymes and ATP content. Furthermore, ANIT significantly decreased the expression of Mrp2, FXR, and Cyp7a1, markedly increased Mrp3 expression in liver. Pretreatment with resveratrol attenuated ANITinduced acute cholestasis and liver injury, and other pathological changes. Pretreatment with ursodeoxycholic acid was less effective. Conclusion: Resveratrol effectively attenuates ANIT-induced acute cholestasis and liver injury in rats, possibly through suppression of neutrophil infiltration, as well as upregulation of expression of hepatic transporters and enzymes, thus decreasing accumulation of bile acids.

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“…Transport of ANIT into the bile by hepatocytes injures intrahepatic BDECs (Dietrich et al, 2001), and exposure of mice to ANIT in the diet causes compensatory biliary hyperplasia, elevation in serum bile acids, portal lymphocytic inflammation, and mild to moderate hepatocellular injury (Tjandra et al, 2000;Xu et al, 2004;Sullivan et al, 2010;Golbar et al, 2013). Prolonged ANIT exposure in mice models progressive liver fibrosis characterized by exaggerated peribiliary collagen deposition (Tjandra et al, 2000;Xu et al, 2004;Sullivan et al, 2010;Golbar et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

The Antifibrinolytic Drug Tranexamic Acid Reduces Liver Injury and Fibrosis in a Mouse Model of Chronic Bile Duct Injury

Joshi

Kopec

Towery

et al. 2014

J Pharmacol Exp Ther

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Hepatic fibrin deposition has been shown to inhibit hepatocellular injury in mice exposed to the bile duct toxicant a-naphthylisothiocyanate (ANIT). Degradation of fibrin clots by fibrinolysis controls the duration and extent of tissue fibrin deposition. Thus, we sought to determine the effect of treatment with the antifibrinolytic drug tranexamic acid (TA) and plasminogen activator inhibitor-1 (PAI-1) deficiency on ANIT-induced liver injury and fibrosis in mice. Plasmin-dependent lysis of fibrin clots was impaired in plasma from mice treated with TA (1200 mg/kg i.p., administered twice daily). Prophylactic TA administration reduced hepatic inflammation and hepatocellular necrosis in mice fed a diet containing 0.025% ANIT for 2 weeks. Hepatic type 1 collagen mRNA expression and deposition increased markedly in livers of mice fed ANIT diet for 4 weeks. To determine whether TA treatment could inhibit this progression of liver fibrosis, mice were fed ANIT diet for 4 weeks and treated with TA for the last 2 weeks. Interestingly, TA treatment largely prevented increased deposition of type 1 collagen in livers of mice fed ANIT diet for 4 weeks. In contrast, biliary hyperplasia/inflammation and liver fibrosis were significantly increased in PAI-1 2/2 mice fed ANIT diet for 4 weeks. Overall, the results indicate that fibrinolytic activity contributes to ANIT diet-induced liver injury and fibrosis in mice. In addition, these proof-of-principle studies suggest the possibility that therapeutic intervention with an antifibrinolytic drug could form a novel strategy to prevent or reduce liver injury and fibrosis in patients with liver disease.

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Role of MRP2 and GSH in intrahepatic cycling of toxins

Cited by 157 publications

References 21 publications

Sweroside ameliorates α-naphthylisothiocyanate-induced cholestatic liver injury in mice by regulating bile acids and suppressing pro-inflammatory responses

Sweroside ameliorates α-naphthylisothiocyanate-induced cholestatic liver injury in mice by regulating bile acids and suppressing pro-inflammatory responses

Resveratrol effectively attenuates α-naphthyl-isothiocyanate-induced acute cholestasis and liver injury through choleretic and anti-inflammatory mechanisms

The Antifibrinolytic Drug Tranexamic Acid Reduces Liver Injury and Fibrosis in a Mouse Model of Chronic Bile Duct Injury

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