Metabonomic and transcriptomic analyses of Tripterygium glycosides tablet-induced hepatotoxicity in rats

Abstract

We aimed to explore novel biomarkers involved in alterations of metabolism and gene expression related to the hepatotoxic effects of Tripterygium glycosides tablet (TGT) in rats. Rats were randomly divided into groups based on oral administration of TGTs for 6 weeks: control, low-dose (9.5 mg/kg), and high-dose (18.9 mg/kg). Serum samples and total liver RNA were subjected to metabonomic and transcriptomic analyses. Thirteen metabolites were significantly up-regulated by liver injury induced by Tripterygium glycosides. Five potential biomarkers were more sensitive than Alanine aminotransferase (ALT) for accurate and timely prediction of hepatic damage. The four metabolic pathways most obviously regulated by hepatotoxicity were D-glutamine and D-glutamate metabolism, alanine, aspartate and glutamate metabolism, ether lipid metabolism, and tryptophan metabolism. Transcriptomics revealed significant differences in 1792 mRNAs and 400 long non-coding (lnc) RNAs. Dysregulated lncRNAs in the TGT-induced hepatotoxicity group were associated with genes involved in amino acid metabolism using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. Up-regulated expression of Ehhadh, Gpt, and Got1, and down-regulated expression of dopa decarboxylase (Ddc), Cyp1a2, Ido2, Aldh1b1, and asparagine synthetase (Asns) was validated by quantitative real-time PCR. This multiomics study has elucidated the relationship between amino metabolism and liver injury, revealing potential biomarkers.

Keywords:

• Tripterygium glycosides tablets
• hepatotoxicity
• metabonomics
• transcriptomics
• biomarkers

Acknowledgments

The authors thank Michelle Kahmeyer-Gabbe, PhD, from Liwen Bianji, Edanz Editing China (www.liwenbianji.cn/ac), for editing the English text of a draft of this manuscript.

Author contributions

All authors have read and approved the final version of the manuscript. All authors confirmed they have contributed to the intellectual content of this article and have met the following four requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved. Zhuoling An, statistical analysis, administrative support; Yuan Sun, statistical analysis; Chen Shi, provision of study material; Lihong Liu, administrative support. Zhuoling An and Lihong Liu have all access to all the data in the study and takes the responsibility for the integrity of the data and the accuracy of the data analysis.

Disclosure statement

Zhuoling An, Yuan Sun, Chen Shi, and Lihong Liu declare that they have no conflict of interest.

Additional information

Funding

This study was supported by grants [81100283 and 81341015] from the National Natural Science Foundation of China, a project [7142065] from the Beijing Municipal Natural Science Foundation, Beijing Municipal Administration of Hospitals’ Youth Programme [QML20150305], and 1351 Talents Program of the Beijing Chao-Yang Hospital [CYXX-2017–31].