Features and Mechanisms of Drug‐Induced Liver Injury

Pessayre, Dominique; Berson, Alain; Fromenty, Bernard

doi:10.1002/9780470372531.ch5

Cited by 5 publications

(7 citation statements)

References 194 publications

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“…Transporters are known to be species‐specific and inhibition can occur at different concentrations cross‐species; however, an absence of BSEP inhibition in zebrafish is unlikely as (1) Bosentan is known to inhibit the activity of BSEP from various species (Fattinger et al ., ) and (2) Driessen et al . () showed histological evidence for the occurrence of cholestasis in zebrafish adults after treatment with the model compounds Tioacetamide, Chlorpromazine and Cyclosporine A; and BSEP inhibition is proposed to be at least part of the mechanism of cholestasis‐induction for these compounds (Pessayre et al ., ). Furthermore, Driessen et al .…”

Section: Discussionmentioning

confidence: 97%

Are zebrafish larvae suitable for assessing the hepatotoxicity potential of drug candidates?

Mesens

Crawford

Menke³

et al. 2015

J of Applied Toxicology

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Drug-induced liver injury (DILI) is poorly predicted by single-cell-based assays, probably because of the lack of physiological interactions with other cells within the liver. An intact whole liver system such as one present in zebrafish larvae could provide added value in a screening strategy for DILI; however, the possible occurrence of other organ toxicities and the immature larval stage of the zebrafish might complicate accurate and fast analysis. We investigated whether expression analysis of liver-specific fatty acid binding protein 10a (lfabp10a) was an appropriate endpoint for assessing hepatotoxic effects in zebrafish larvae. It was found that expression analysis of lfabp10a was a valid marker, as after treatment with hepatotoxicants, dose-response curves could be obtained and statistically significant abnormal lfabp10 expression levels correlated with hepatocellular histopathological changes in the liver. However, toxicity in other vital organs such as the heart could impact liver outgrowth and thus had to be assessed concurrently. Whether zebrafish larvae were suitable for assessing human relevant drug-induced hepatotoxicity was assessed with hepatotoxicants and non-hepatotoxicants that have been marketed for human use and classified according to their mechanism of toxicity. The zebrafish larva showed promising predictivity towards a number of mechanisms and was capable of distinguishing between hepatotoxic and non-hepatotoxic chemical analogues, thus implying its applicability as a potential screening model for DILI.

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Section: Discussionmentioning

confidence: 97%

Are zebrafish larvae suitable for assessing the hepatotoxicity potential of drug candidates?

Mesens

Crawford

Menke³

et al. 2015

J of Applied Toxicology

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“…44,45 Inhibition of β-oxidation of mitochondrial fatty acids reduces the amount of NADH and FADH 2 available for oxidative phosphorylation that, in turn, reduces ATP production. 46 Mitochondrial DNA encodes 13 components of the electron transport chain; damage that occurs to mitochondrial DNA can have a variety of downstream effects depending upon where it occurs. 36,46 It should be noted, however, that there is the potential that multiple, competing, mechanisms could initiate mitochondrial toxicity observed for a single (group of) chemical(s), i.e., one chemical may induce several MIEs.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Briefly stated, chemicals that inhibit the electron transport chain can do so either by direct binding to the complexes of the electron transport chain or ATP synthase or by acting as an alternative electron acceptor. ,, The inhibition of electron flow along the electron transport chain by both of these mechanisms induces the formation of reactive oxygen species, resulting in oxidative stress. ,, Uncouplers of oxidative phosphorylation induce mitochondrial toxicity by shuttling protons into the mitochondrial matrix, via the inner mitochondrial membrane, bypassing ATP synthase. This assisted transport of protons back into the matrix dissipates the electrochemical potential, resulting in the loss of ATP production and, ultimately, cell death. ,,,,− Induction of the membrane permeability transition increases the permeability of the inner mitochondrial membrane to low molecular weight solutes (<1500 Da), leading to a disruption of the electron transport chain, loss of membrane potential, and swelling of both the inner and outer mitochondrial membranes. , Inhibition of β-oxidation of mitochondrial fatty acids reduces the amount of NADH and FADH 2 available for oxidative phosphorylation that, in turn, reduces ATP production . Mitochondrial DNA encodes 13 components of the electron transport chain; damage that occurs to mitochondrial DNA can have a variety of downstream effects depending upon where it occurs. , It should be noted, however, that there is the potential that multiple, competing, mechanisms could initiate mitochondrial toxicity observed for a single (group of) chemical(s), i.e., one chemical may induce several MIEs.…”

Section: Introductionmentioning

confidence: 99%

Development of an in Silico Profiler for Mitochondrial Toxicity

Nelms

Mellor

Cronin

et al. 2015

Chem. Res. Toxicol.

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This study outlines the analysis of mitochondrial toxicity for a variety of pharmaceutical drugs extracted from Zhang et al. These chemicals were grouped into categories based upon structural similarity. Subsequently, mechanistic analysis was undertaken for each category to identify the Molecular Initiating Event driving mitochondrial toxicity. The mechanistic information elucidated during the analysis enabled mechanism-based structural alerts to be developed and combined together to form an in silico profiler. This profiler is envisaged to be used to develop chemical categories based upon similar mechanisms as part of the Adverse Outcome Pathway paradigm. Additionally, the profiler could be utilised in screening large dataset in order to identify chemicals with the potential to induce mitochondrial toxicity.

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“…34 In this study, Hep3B cells were more sensitive to the inhibitory effects exerted by blue cohosh compounds, relative to T47D cells (Figures 1A–1D). As Hep3B cells are of neoplasmic origin, evaluation of these C. thalictroides metabolites in primary hepatocytes will be required to distinguish some form of tumor cell-selective, rather than liver cell-selective, cytotoxicity.…”

Section: Resultsmentioning

confidence: 53%

Toxins in Botanical Dietary Supplements: Blue Cohosh Components Disrupt Cellular Respiration and Mitochondrial Membrane Potential

Datta¹,

Mahdi²,

Ali³

et al. 2013

J. Nat. Prod.

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Certain botanical dietary supplements have been associated with idiosyncratic organ-specific toxicity. Similar toxicological events, caused by drug-induced mitochondrial dysfunction, have forced the withdrawal or U.S. FDA “Black Box” warnings of major pharmaceuticals. To assess the potential mitochondrial liability of botanical dietary supplements, extracts from 352 authenticated plant samples used in traditional Chinese, Ayurvedic, and Western herbal medicine were evaluated for the ability to disrupt cellular respiration. Blue cohosh (Caulophyllum thalictroides) methanol extract exhibited mitochondriotoxic activity. Used by some U.S. midwives to help induce labor, blue cohosh has been associated with perinatal stroke, acute myocardial infarction, congestive heart failure, multiple organ injury, and neonatal shock. The potential link between mitochondrial disruption and idiosyncratic herbal intoxication prompted further examination. The C. thalictroides methanol extract and three saponins, cauloside A (1), saponin PE (2), and cauloside C (3) exhibited concentration- and time-dependent mitochondriotoxic activities. Upon treatment, cell respiration rate rapidly increased and then dramatically decreased within minutes. Mechanistic studies revealed that C. thalictroides constituents impair mitochondrial function by disrupting membrane integrity. These studies provide a potential etiological link between this mitochondria-sensitive form of cytotoxicity and idiosyncratic organ damage.

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Features and Mechanisms of Drug‐Induced Liver Injury

Cited by 5 publications

References 194 publications

Are zebrafish larvae suitable for assessing the hepatotoxicity potential of drug candidates?

Are zebrafish larvae suitable for assessing the hepatotoxicity potential of drug candidates?

Development of an in Silico Profiler for Mitochondrial Toxicity

Toxins in Botanical Dietary Supplements: Blue Cohosh Components Disrupt Cellular Respiration and Mitochondrial Membrane Potential

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