Comprehensive analysis of transcriptomics and metabolomics to understand triptolide-induced liver injury in mice

•An integrated application of transcriptomics and metabolomics methods was conducted to reveal mechanism of triptolide-induced liver toxicity.•Triptolide-induced toxicity occurred in a dose- and time-dependent manners.•Apoptosis might be responsible for triptolide-induced liver toxicity and not necr...

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Published in:Toxicology letters Vol. 333; pp. 290 - 302
Main Authors: Zhao, Jie, Xie, Cen, Wang, Kanglong, Takahashi, Shogo, Krausz, Kristopher W., Lu, Dasheng, Wang, Qiong, Luo, Yuhong, Gong, Xianqiong, Mu, Xiyan, Wang, Qiao, Su, Suwen, Gonzalez, Frank J.
Format: Journal Article
Language:English
Published: Netherlands Elsevier B.V 15.10.2020
Subjects:
Acylcarnitine
Animals
Apoptosis
Apoptosis - drug effects
Apoptosis - genetics
Chemical and Drug Induced Liver Injury - genetics
Chemical and Drug Induced Liver Injury - metabolism
Chemical and Drug Induced Liver Injury - pathology
Diterpenes - toxicity
Dose-Response Relationship, Drug
Epoxy Compounds - toxicity
Gene Expression Profiling
Metabolome - drug effects
Metabolome - genetics
Metabolomics
Mice
Mice, Inbred C57BL
Mice, Knockout
Necroptosis - drug effects
Necroptosis - genetics
Phenanthrenes - toxicity
Transcriptome - drug effects
Transcriptomics
Triptolide
Metabolomics
Tnfα
Acylcarnitine
ALT
FPKM
MPT
TUNEL
PI3K
Transcriptomics
Triptolide
CCK-8
ESI
AST
MLKL
RIPK3
MS
H&E
TWHF
Bim
OPLS-DA
DMARD
PLS-DA
MAPK
UPLC
RIN
Bax
Apoptosis
ISSN:0378-4274, 1879-3169, 1879-3169
Online Access:Get full text
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Summary:•An integrated application of transcriptomics and metabolomics methods was conducted to reveal mechanism of triptolide-induced liver toxicity.•Triptolide-induced toxicity occurred in a dose- and time-dependent manners.•Apoptosis might be responsible for triptolide-induced liver toxicity and not necroptosis.•PI3K/AKT, MAPK, TNFα and p53 signaling pathways might be the vital steps in triptolide-induced hepatocyte apoptosis.•Acylcarnitines could be considered as potential biomarkers. Triptolide, a major active component of Triptergium wilfordii Hook. f, is used in the treatment of autoimmune disease. However, triptolide is associated with severe adverse reactions, especially hepatotoxicity, which limits its clinical application. To examine the underlying mechanism of triptolide-induced liver injury, a combination of dose- and time-dependent toxic effects, RNA-seq and metabolomics were employed. Triptolide-induced toxicity occurred in a dose- and time-dependent manners and was characterized by apoptosis and not necroptosis. Transcriptomics profiles of the dose-dependent response to triptolide suggested that PI3K/AKT, MAPK, TNFα and p53 signaling pathways were the vital steps in triptolide-induced hepatocyte apoptosis. Metabolomics further revealed that glycerophospholipid, fatty acid, leukotriene, purine and pyrimidine metabolism were the major metabolic alterations after triptolide exposure. Finally, acylcarnitines were identified as potential biomarkers for the early detection of triptolide-induced liver injury.
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These authors contributed equally to this work.
ISSN:0378-4274
1879-3169
1879-3169
DOI:10.1016/j.toxlet.2020.08.007