Toxicity and intracellular accumulation of bile acids in sandwich-cultured rat hepatocytes: Role of glycine conjugates

Chatterjee, Sagnik; Bijsmans, Ingrid T.G.W.; Mil, Saskia W.C. van; Augustijns, Patrick; Annaert, Pieter

doi:10.1016/j.tiv.2013.10.020

Cited by 39 publications

(26 citation statements)

References 45 publications

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“…We applied the parameters for the unconjugated bile acids measured in the experiments to the conjugated bile acids in DILIsym®; for example, we used the unconjugated LCA parameters to describe the toxicity of LCA amide and sulfate conjugates. While some data exist describing the relationship between intracellular amide- and sulfate-conjugated bile acids and toxicity (Chatterjee et al, 2013), these are not enough to justify using different toxicity parameters for conjugated and unconjugated bile acids; this is an area of potential refinement for DILIsym®.…”

Section: Methodsmentioning

confidence: 99%

Exploring BSEP inhibition-mediated toxicity with a mechanistic model of drug-induced liver injury

et al. 2014

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Inhibition of the bile salt export pump (BSEP) has been linked to incidence of drug-induced liver injury (DILI), presumably by the accumulation of toxic bile acids in the liver. We have previously constructed and validated a model of bile acid disposition within DILIsym®, a mechanistic model of DILI. In this paper, we use DILIsym® to simulate the DILI response of the hepatotoxic BSEP inhibitors bosentan and CP-724,714 and the non-hepatotoxic BSEP inhibitor telmisartan in humans in order to explore whether we can predict that hepatotoxic BSEP inhibitors can cause bile acid accumulation to reach toxic levels. We also simulate bosentan in rats in order to illuminate potential reasons behind the lack of toxicity in rats compared to the toxicity observed in humans. DILIsym® predicts that bosentan, but not telmisartan, will cause mild hepatocellular ATP decline and serum ALT elevation in a simulated population of humans. The difference in hepatotoxic potential between bosentan and telmisartan is consistent with clinical observations. However, DILIsym® underpredicts the incidence of bosentan toxicity. DILIsym® also predicts that bosentan will not cause toxicity in a simulated population of rats, and that the difference between the response to bosentan in rats and in humans is primarily due to the less toxic bile acid pool in rats. Our simulations also suggest a potential synergistic role for bile acid accumulation and mitochondrial electron transport chain (ETC) inhibition in producing the observed toxicity in CP-724,714, and suggest that CP-724,714 metabolites may also play a role in the observed toxicity. Our work also compares the impact of competitive and noncompetitive BSEP inhibition for CP-724,714 and demonstrates that noncompetitive inhibition leads to much greater bile acid accumulation and potential toxicity. Our research demonstrates the potential for mechanistic modeling to contribute to the understanding of how bile acid transport inhibitors cause DILI.

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Section: Methodsmentioning

confidence: 99%

Exploring BSEP inhibition-mediated toxicity with a mechanistic model of drug-induced liver injury

et al. 2014

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“…Bile acids play an important role in the enterohepatic system, but the corresponding cytotoxicity to hepatocytes should also be addressed [1,2] . Numerous studies have suggested that the intrahepatic accumulation of bile acids may directly or indirectly cause further damage to the liver [3] .…”

Section: Introductionmentioning

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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“…Interestingly, hepatic TBA content increased as a result of HC feeding, with no significant further increment following BDL as opposed to chow fed mice, which exhibit a time-dependent increase in liver TBA, reaching similar values observed in HC fed animals at day three. The toxic effect of bile acids is well documented [21, 29, 30] and accumulation in the liver is one of the main factors associated with cholestasis.…”

Section: Discussionmentioning

confidence: 99%

Liver Cholesterol Overload Aggravates Obstructive Cholestasis by Inducing Oxidative Stress and Premature Death in Mice

Nuño‐Lámbarri

Domínguez‐Pérez

Baulies-Domenech

et al. 2016

Oxidative Medicine and Cellular Longevity

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Nonalcoholic steatohepatitis is one of the leading causes of liver disease. Dietary factors determine the clinical presentation of steatohepatitis and can influence the progression of related diseases. Cholesterol has emerged as a critical player in the disease and hence consumption of cholesterol-enriched diets can lead to a progressive form of the disease. The aim was to investigate the impact of liver cholesterol overload on the progression of the obstructive cholestasis in mice subjected to bile duct ligation surgery. Mice were fed with a high cholesterol diet for two days and then were subjected to surgery procedure; histological, biochemical, and molecular analyses were conducted to address the effect of cholesterol in liver damage. Mice under the diet were more susceptible to damage. Results show that cholesterol fed mice exhibited increased apoptosis and oxidative stress as well as reduction in cell proliferation. Mortality following surgery was higher in HC fed mice. Liver cholesterol impairs the repair of liver during obstructive cholestasis and aggravates the disease with early fatal consequences; these effects were strongly associated with oxidative stress.

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Toxicity and intracellular accumulation of bile acids in sandwich-cultured rat hepatocytes: Role of glycine conjugates

Cited by 39 publications

References 45 publications

Exploring BSEP inhibition-mediated toxicity with a mechanistic model of drug-induced liver injury

Exploring BSEP inhibition-mediated toxicity with a mechanistic model of drug-induced liver injury

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

Liver Cholesterol Overload Aggravates Obstructive Cholestasis by Inducing Oxidative Stress and Premature Death in Mice

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