BML-257, a Small Molecule that Protects against Drug-Induced Liver Injury in Zebrafish

Jagtap, Urmila; Basu, S.; Lokhande, Lavanya; Bharti, Nikhil; Sachidanandan, Chetana

doi:10.1021/acs.chemrestox.2c00100

Cited by 3 publications

(4 citation statements)

References 38 publications

(60 reference statements)

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“…It was demonstrated that the administration of 10 mM INH between 3-4 dpf resulted in liver size decrease (Jagtap et al, 2022). Another study reported induction of apoptosis upon exposure to 6 mM INH between 4-5 dpf (Higuchi et al, 2021).…”

Section: Isoniazid-induced Liver Enlargement Only At 5-7 Dpf Stagementioning

confidence: 99%

“…DILI remains one of the most challenging issues in the discovery and pre/postmarketing stages of drug development (Andrade et al, 2019). Zebrafish larva due to it being time and costeffective, has attracted interest as an in vivo model for prediction of a drug candidate's hepatotoxicity potential (Jagtap et al, 2022). The rapid maturation of the liver within 5 days post fertilization (dpf), transparency of the larvae, easy application of test compounds, and the possibility for medium-throughput live imaging are among attractive features of zebrafish (Chu & Sadler, 2009;Katoch & Patial, 2021;Vliegenthart et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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The developmental stage is a critical parameter for accurate assessment of the drug-induced liver injury (DILI) potentials of drugs with the zebrafish larval liver model

Çakan Akdoğan,

Bilgi

2024

Biotech Studies

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Prediction of drug-induced liver injury (DILI) potential of drugs is one of the most challenging issues of drug development. Zebrafish larvae provide an in vivo and robust test platform. Due to the ease of handling developing larvae between 2 - 5 days post fertilization (dpf) has been extensively used as a DILI test model. However, the liver is not fully functional at this stage. Here, the importance of larval liver maturation was tested by applying selected known DILI-rank drugs to liver reporter zebrafish between 2-5 dpf and 5-7 dpf. Acetaminophen (most-DILI) treatment caused a significant dose-dependent reduction in liver size only at the early stage. Isoniazid (most-DILI) administration after liver maturation induced hepatomegaly, while it induced liver size reduction between 2-5 dpf. Chlorambucil (less-DILI) treatment induced opposing effects on liver size, in the two stages tested. A non-DILI agent chloramphenicol did not induce any liver size change in either larval stage. Clinical observations were better reproduced when isoniazid and chlorambucil were administered after liver maturation. Our findings show that often-overlooked liver maturity status is a critical parameter for the evaluation of DILI.

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Section: Isoniazid-induced Liver Enlargement Only At 5-7 Dpf Stagementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The developmental stage is a critical parameter for accurate assessment of the drug-induced liver injury (DILI) potentials of drugs with the zebrafish larval liver model

Çakan Akdoğan,

Bilgi

2024

Biotech Studies

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“…Expression of bacterial nitroreductase gene in hepatocytes is used for targeted ablation of liver cells via exposure to prodrug metronidazole [55]. Recently this tool has been used to identify hepatoprotective small molecules in a screen and BML-257, an AKT inhibitor, was found to provide protection against liver damage caused by acetaminophen (APAP) and isoniazid [63]. Moreover, according to a recent review, the role of ferroptosis in DILI, when compared to other liver diseases, remains relatively unexplored with most of the research being based on APAP induced DILI [64].…”

Section: Reporter Transgenic Zebrafish Lines For the Accurate Assessm...mentioning

confidence: 99%

Zebrafish as a model for drug induced liver injury: state of the art and beyond

et al. 2023

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Zebrafish as a preclinical drug induced liver injury (DILI) model provides multiple advantages ranging from ease of breeding and maintenance, availability of different strains and transgenic fish amenable to study liver function, and highly conserved liver structure and function with the human liver. In this review, the authors have aimed to provide an account of the metabolic enzymes that take roles in drug detoxification in both human and zebrafish in a comparative manner and exemplify several recent models in studying liver functionality. Moreover, the authors emphasize the difficulties associated with studying idiosyncratic DILI in preclinical models and propose that zebrafish could be an important complement to mice in testing functions of genes that are associated with DILI with respect to different drugs in human genome-wide association studies (GWAS) Catalog. Finally, this review highlights the state-of-the-art in the development of novel transgenic reporter strains that can be used to study degree and molecular mechanisms of hepatotoxicity caused by drugs in zebrafish. All of these will help researchers to use effectively the available resources in the zebrafish DILI models, while advocating potential leads that can be taken to provide advancements in a better understanding and treatment of DILI.

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“…It is thought that depletion of glutathione (GSH) by NAPQI causes oxidative stress, resulting in hepatotoxicity. APAP toxicity has also been reported in adult zebrafish and larvae [ 15 , 16 ]. North et al [ 17 ] showed that APAP caused reduction of liver size through inducing apoptosis in larval zebrafish and that the combination of prostaglandin E2 (PGE2) and N -acetylcysteine (NAC), a precursor of GSH, reversed APAP toxicity in the liver.…”

Section: Introductionmentioning

confidence: 99%

Transgenic Zebrafish Expressing Rat Cytochrome P450 2E1 (CYP2E1): Augmentation of Acetaminophen-Induced Toxicity in the Liver and Retina

Sato

Dong

Nakamura

et al. 2023

IJMS

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Metabolic activation is the primary cause of chemical toxicity including hepatotoxicity. Cytochrome P450 2E (CYP2E) is involved in this process for many hepatotoxicants, including acetaminophen (APAP), one of the most common analgesics and antipyretics. Although the zebrafish is now used as a model for toxicology and toxicity tests, the CYP2E homologue in zebrafish has not been identified yet. In this study, we prepared transgenic zebrafish embryos/larvae expressing rat CYP2E1 and enhanced green fluorescent protein (EGFP) using a β-actin promoter. Rat CYP2E1 activity was confirmed by the fluorescence of 7-hydroxycoumarin (7-HC), a metabolite of 7-methoxycoumarin that was specific for CYP2 in transgenic larvae with EGFP fluorescence (EGFP [+]) but not in transgenic larvae without EGFP fluorescence (EGFP [−]). APAP (2.5 mM) caused reduction in the size of the retina in EGFP [+] larvae but not in EGFP [−] larvae, while APAP similarly reduced pigmentation in both larvae. APAP at even 1 mM reduced the liver size in EGFP [+] larvae but not in EGFP [−] larvae. APAP-induced reduction of liver size was inhibited by N-acetylcysteine. These results suggest that rat CYP2E1 is involved in some APAP-induced toxicological endpoints in the retina and liver but not in melanogenesis of the developing zebrafish.

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BML-257, a Small Molecule that Protects against Drug-Induced Liver Injury in Zebrafish

Cited by 3 publications

References 38 publications

The developmental stage is a critical parameter for accurate assessment of the drug-induced liver injury (DILI) potentials of drugs with the zebrafish larval liver model

The developmental stage is a critical parameter for accurate assessment of the drug-induced liver injury (DILI) potentials of drugs with the zebrafish larval liver model

Zebrafish as a model for drug induced liver injury: state of the art and beyond

Transgenic Zebrafish Expressing Rat Cytochrome P450 2E1 (CYP2E1): Augmentation of Acetaminophen-Induced Toxicity in the Liver and Retina

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