Inhibition of bile canalicular network formation in rat sandwich cultured hepatocytes by drugs associated with risk of severe liver injury

Takemura, Akinori; Izaki, Aya; Sekine, Satoshi; Ito, Kousei

doi:10.1016/j.tiv.2016.05.016

Cited by 18 publications

(10 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The mechanisms of this initial drug stress may be very similar to those for intrinsic DILI compounds. This is supported by the recent development of several cell‐based assays that appear to have some sensitivity and specificity for predicting idiosyncratic DILI liability using hepatocytes or hepatocyte‐like cell lines in the absence of immune cells . Many of these approaches rely on endpoints based on the same three mechanisms that typically underlie intrinsic DILI: mitochondrial dysfunction, oxidative stress, and alterations in bile acid homeostasis.…”

Section: Idiosyncratic Dilimentioning

confidence: 99%

Drug‐induced liver injury: Advances in mechanistic understanding that will inform risk management

Mosedale

Watkins

2017

Clin Pharma and Therapeutics

173

130

View full text Add to dashboard Cite

Drug-induced liver injury (DILI) is a major public health problem. Intrinsic (dose-dependent) DILI associated with acetaminophen overdose is the number one cause of acute liver failure in the US. However the most problematic type of DILI impacting drug development is idiosyncratic, occurring only very rarely among treated patients and often only after several weeks or months of treatment with the offending drug. Recent advances in our understanding of the pathogenesis of DILI suggest that three mechanisms may underlie most hepatocyte effects in response to both intrinsic and idiosyncratic DILI drugs: mitochondrial dysfunction, oxidative stress, and alterations in bile acid homeostasis. However, in some cases, hepatocyte stress promotes an immune response that results in clinically important idiosyncratic DILI. This review discusses recent advances in our understanding of the pathogenesis of both intrinsic and idiosyncratic DILI as well as emerging tools and techniques that will likely improve DILI risk identification and management.

show abstract

Section: Idiosyncratic Dilimentioning

confidence: 99%

Drug‐induced liver injury: Advances in mechanistic understanding that will inform risk management

Mosedale

Watkins

2017

Clin Pharma and Therapeutics

173

130

View full text Add to dashboard Cite

show abstract

“…Rat hepatocytes were isolated using a two-step perfusion method, as reported previously (Takemura et al, 2016). The cells were seeded onto collagen-coated tissue culture plates at a density of 4.125 × 10 4 cells/well in 0.1 mL of plating medium in 96-well plates.…”

Section: Hepatocyte Isolation Purification and Culturementioning

confidence: 99%

Increased susceptibility to troglitazone-induced mitochondrial permeability transition in type 2 diabetes mellitus model rat

et al. 2018

Self Cite

View full text Add to dashboard Cite

Troglitazone, a member of the thiazolidinedione class of antidiabetic drugs, was withdrawn from the market because it causes severe liver injury. One of the mechanisms for this adverse effect is thought to be mitochondrial toxicity. To investigate the characteristics of troglitazone-induced liver toxicity in more depth, the toxicological effects of troglitazone on hepatocytes and liver mitochondria were investigated using a rat model of type 2 diabetes mellitus (T2DM). Troglitazone was found to increase mitochondrial permeability transition (MPT) in the liver mitochondria of diabetic rats to a greater extent than in control rats, whereas mitochondrial membrane potential and oxidative phosphorylation were not affected. To identify the factors associated with this increase in susceptibility to MPT in diabetic rats, we assessed the oxidative status of the liver mitochondria and found a decrease in mitochondrial glutathione content and an increase in phospholipid peroxidation. Moreover, incorporation of oxidized cardiolipin, a mitochondrion-specific phospholipid, was involved in the troglitazone-induced alteration in susceptibility to MPT. In conclusion, liver mitochondria display disease-associated mitochondrial lipid peroxidation in T2DM, which facilitates the higher susceptibility to troglitazone-induced MPT. Thus, greater susceptibility of liver mitochondria may be a host factor leading to troglitazone-induced hepatotoxicity in T2DM.

show abstract

“…Troglitazone, the first oral peroxisome proliferator-associated receptor gamma agonist for the treatment of type 2 diabetes, was marketed in March 1997 and was removed from the U.S. market 36 months later after 90 cases of liver failure. Troglitazone is often regarded as a prototypical drug for research to further the mechanistic understanding of idiosyncratic drug toxicity as well as the development of predictive approaches for the identification of structures with idiosyncratic hepatotoxic potential in drug development (Goda et al, 2016;Takemura et al, 2016;Kim et al, 2017a;Mak et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Permeabilized Cryopreserved Human Hepatocytes as an Exogenous Metabolic System in a Novel Metabolism-Dependent Cytotoxicity Assay for the Evaluation of Metabolic Activation and Detoxification of Drugs Associated with Drug-Induced Liver Injuries: Results with Acetaminophen, Amiodarone, Cyclophosphamide, Ketoconazole, Nefazodone, and Troglitazone

Hong

2021

Drug Metab Dispos

View full text Add to dashboard Cite

Inhibition of bile canalicular network formation in rat sandwich cultured hepatocytes by drugs associated with risk of severe liver injury

Cited by 18 publications

References 53 publications

Drug‐induced liver injury: Advances in mechanistic understanding that will inform risk management

Drug‐induced liver injury: Advances in mechanistic understanding that will inform risk management

Increased susceptibility to troglitazone-induced mitochondrial permeability transition in type 2 diabetes mellitus model rat

Contact Info

Product

Resources

About