Evaluation of the Potential Risk of Drugs to Induce Hepatotoxicity in Human—Relationships between Hepatic Steatosis Observed in Non-Clinical Toxicity Study and Hepatotoxicity in Humans-

Goda, Keisuke; Kobayashi, Akio; Takahashi, Akiko; Takahashi, Tadakazu; Saito, Kosuke; Maekawa, Keiko; Saito, Yoshiro; Sugai, Shoichiro

doi:10.3390/ijms18040810

Cited by 15 publications

(18 citation statements)

References 29 publications

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“…In addition, the incidence and severity of fatty change in the periportal hepatocytes were increased in the liver in the CBZ-treated SDT fatty rats when compared with the CBZ-treated SD rats. Fatty change of the hepatocytes (steatosis) in non-clinical toxicity studies of drug candidates can be regarded as a critical finding for the estimation of their potential risk to induce DILI in humans when the fatty change is induced by mitochondrial dysfunction (Goda et al, 2017). The mitochondrial dysfunction may have occurred in the hepatocytes in the CBZ-treated SDT fatty rats.…”

Section: Discussionmentioning

confidence: 99%

Carbamazepine-induced liver injury using type 2 diabetes Spontaneously Diabetic Torii-Leprfa (SDT fatty) rats as a model for human type 2 diabetes

Takahashi

Matsuura

Toyoda

et al. 2019

Fundam. Toxicol. Sci.

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The diabetic state is considered to be one of the risk factors of drug-induced liver injury (DILI) because of the lower levels of glutathione for detoxification by conjugation with drugs. Carbamazepine (CBZ)-induced hepatotoxicity in humans is rare and unpredictable with the present state of knowledge, but it is somehow related to disturbance of glutathione metabolism, although data in this regard are limited. In order to estimate the potential risk of DILI in patients with type 2 diabetes mellitus (T2DM), we investigated the liver injury from CBZ, which is often used in the treatment of painful diabetic neuropathy in diabetic patients, using SD rats and Spontaneously Diabetic Torii-Lepr fa (SDT fatty) rats as a model for human T2DM. The SDT fatty rats appropriately mimic the diabetic state in humans and have similar profiles of glucose metabolism, hepatic function tests and glutathione synthesis to those in patients with T2DM. Short-term oral dosing with CBZ to the SDT fatty rats revealed that liver injury was detected in the SDT fatty rats but not in the SD rats and the difference was considered to be due to lower hepatic detoxification of the metabolites of CBZ by depleted hepatic glutathione synthesis. In conclusion, the potential for CBZ to induce liver injury is considered to be higher in diabetic patients than in non-diabetic humans.

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Section: Discussionmentioning

confidence: 99%

Carbamazepine-induced liver injury using type 2 diabetes Spontaneously Diabetic Torii-Leprfa (SDT fatty) rats as a model for human type 2 diabetes

Takahashi

Matsuura

Toyoda

et al. 2019

Fundam. Toxicol. Sci.

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“…Macro and microvesicular steatosis due to mitochondrial dysfunction. 6,7 May or may not be accompanied by steatohepatitis features (ballooning, inflammation, etc. ).…”

Section: Referencesmentioning

confidence: 99%

Drug-induced chronic liver injury

Dakhoul

Ghabril

Chalasani

2018

Journal of Hepatology

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“…12 Substances that inhibit mitochondrial function are of interest to the pharmaceutical industry since this organelle represents an off-target toxicity that has resulted in the withdrawal of certain drugs (e.g., Tacrine) from the market. 13,14 Likewise, the mitochondrial respiratory chain represents a potential target for cancer therapies, and the ability to rapidly identify substances that affect the respiratory complexes would be of value in the development of novel chemotherapeutic agents. 12 In addition to xenobiotic-mediated dysfunction, inherited mutations in mitochondrial DNA result in damage to many key organ systems (nervous system, liver, eyes, kidneys, etc.).…”

Section: Introductionmentioning

confidence: 99%

Hybrid Machine-Learning/SMARTS Profiling Model for Mitochondrial Inhibition

Wijeyesakere

Wilson

Auernhammer

et al. 2019

Applied In Vitro Toxicology

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Introduction: We are using big-data mining to develop computational models that predict whether previously uncharacterized compounds will or will not target important biological pathways. Mitochondria play essential life-sustaining roles, with their dysfunction linked to diverse pathologies. Materials and Methods: We built a mitochondrial inhibition model that combines molecular scaffolding and fingerprinting of a large database compiled primarily from in vitro high-throughput screening (HTS) data. We refined the model to include SMARTS profilers for known subtarget features (i.e., inhibition of Complexes I-V or uncoupling through protonophore action). For some of these, compound substructures capable of metabolic transformation to cyanide or hydrogen sulfide were identified and included based on potential for high in vivo toxicity despite lack of activity in cell-based platforms that appear to lack critical metabolic pathways and/or cell sensitivity. Results and Discussion: The model is comprehensive-the machine-learning component has high sensitivity (80.3%) and accuracy (79.4%), together with positive and negative predictive values of 60.9% and 90.7%, respectively. Model predictivity is limited by the heterogeneity of mechanistic mitochondrial targets, as well as sensitivity of HTS assays and domain of tested compounds. When applied to a database of human therapeutics withdrawn from the market due to liver injury, it identified all compounds demonstrated to target mitochondria. Conclusions: The model can be used in an integrated approach to complement early in vitro screening and as a covariate in Quantitative Structure Activity Relationship (QSAR) models for systemic toxicological end points.

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Evaluation of the Potential Risk of Drugs to Induce Hepatotoxicity in Human—Relationships between Hepatic Steatosis Observed in Non-Clinical Toxicity Study and Hepatotoxicity in Humans-

Cited by 15 publications

References 29 publications

Carbamazepine-induced liver injury using type 2 diabetes Spontaneously Diabetic Torii-<i>Lepr<sup>fa</sup></i> (SDT fatty) rats as a model for human type 2 diabetes

Carbamazepine-induced liver injury using type 2 diabetes Spontaneously Diabetic Torii-<i>Lepr<sup>fa</sup></i> (SDT fatty) rats as a model for human type 2 diabetes

Drug-induced chronic liver injury

Hybrid Machine-Learning/SMARTS Profiling Model for Mitochondrial Inhibition

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