PUBLICATION
Metabolic competency of larval zebrafish in drug-induced liver injury: a case study of acetaminophen poisoning
- Authors
- Chen, Y., Song, W., Ge, W., Yan, R.
- ID
- ZDB-PUB-220810-5
- Date
- 2022
- Source
- Toxicological sciences : an official journal of the Society of Toxicology 189(2): 175-185 (Journal)
- Registered Authors
- Ge, Wei
- Keywords
- acetaminophen, bioactivation, drug-induced liver injury, liver imaging, metabolic capacity, zebrafish model
- MeSH Terms
-
- Acetaminophen*/poisoning
- Acetylcysteine/pharmacology
- Animals
- Benzoquinones
- Chemical and Drug Induced Liver Injury*/metabolism
- Cytochrome P-450 Enzyme System/metabolism
- Glutathione/metabolism
- Imines
- Larva/metabolism
- Liver
- Mammals/metabolism
- Sulfates/metabolism
- Sulfates/pharmacology
- Zebrafish/metabolism
- PubMed
- 35944217 Full text @ Toxicol. Sci.
Citation
Chen, Y., Song, W., Ge, W., Yan, R. (2022) Metabolic competency of larval zebrafish in drug-induced liver injury: a case study of acetaminophen poisoning. Toxicological sciences : an official journal of the Society of Toxicology. 189(2):175-185.
Abstract
Larval zebrafish is emerging as a new model organism for studying drug-induced liver injury (DILI) with superiorities in visual assessment, genetic engineering as well as high throughput. Metabolic bioactivation to form reactive intermediates is a common event that triggers DILI. This study first addressed the correlation between acetaminophen metabolism and hepatotoxicity in zebrafish larvae (3 days post-fertilization) and demonstrated the occurrence of cytochrome P450 enzymes-mediated APAP bioactivation at early developmental stage through characterizing the dose-effect (0-1.6 mg/mL) and the time-course (0-72 h) of liver injury and metabolism in the AB strain and LiPan transgenic line Tg(lfabp10a: DsRed; elaA: egfp) expressing liver-specific fluorescent protein. APAP caused multi-organ developmental retardation and elicited dose- and time-dependent hepatotoxicity. Liver imaging revealed significant changes earlier than histological and biochemical measurements. APAP bioactivation in larval zebrafish was first confirmed by the detection of the glutathione conjugate of the reactive intermediate NAPQI (NAPQI-GSH) and subsequent mercapturate derivatives NAPQI-cysteine and NAPQI-N-acetylcysteine after even short (0.5-hour post exposure) or low (0.2 mg/mL) APAP exposure. APAP overdose impaired metabolic function, in particular sulfation, while facilitated GSH depletion and APAP sulfate excretion. Meanwhile, APAP displayed triphasic accumulation in the larvae, agreeing with fluctuating metabolic capabilities with sulfation dominating the early larval developmental stage. Most importantly, the dose-response effects and time-course of APAP accumulation and metabolism agree well with those of the liver injury development. Overall, larval zebrafish has developed mammalian-like metabolic function, enabling it an ideal model organism for high throughput screening hepatotoxicity and mechanistic study of bioactivation-based DILI.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping