The role of vitamin D3 upregulated protein 1 in thioacetamide-induced mouse hepatotoxicity

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Title
The role of vitamin D3 upregulated protein 1 in thioacetamide-induced mouse hepatotoxicity
Author(s)
Hyo Jung Kwon; J H Lim; J T Han; S B Lee; Woon Kee YoonKi Hoan Nam; In Pyo Choi; D Y Kim; Young Suk WonHyoung-Chin Kim
Bibliographic Citation
Toxicology and Applied Pharmacology, vol. 248, no. 3, pp. 277-284
Publication Year
2010
Abstract
Thioacetamide (TA) is a commonly used drug that can trigger acute hepatic failure (AHF) through generation of oxidative stress. Vitamin D3 upregulated protein 1 (VDUP1) is an endogenous inhibitor of thioredoxin, a ubiquitous thiol oxidoreductase, that regulates cellular redox status. In this study, we investigated the role of VDUP1 in AHF using a TA-induced liver injury model. VDUP1 knockout (KO) and wild-type (WT) mice were subjected to a single intraperitoneal TA injection, and various parameters of hepatic injury were assessed. VDUP1 KO mice displayed a significantly higher survival rate, lower serum alanine aminotransferase and aspartate aminotransferase levels, and less hepatic damage, compared to WT mice. In addition, induction of apoptosis was decreased in VDUP1 KO mice, with the alteration of caspase-3 and -9 activities, Bax-to-Bcl-2 expression ratios, and mitogen activated protein kinase (MAPK) signaling pathway. Importantly, analysis of TA bioactivation revealed lower plasma clearance of TA and covalent binding of [14C]TA to liver macromolecules in VDUP1 KO mice. Furthermore, the level of oxidative stress was significantly less in VDUP1 KO mice than in their WT counterparts, as evident from lipid peroxidation assay. These results collectively indicate that VDUP1 deficiency protects against TA-induced acute liver injury via lower bioactivation of TA and antioxidant effects.
Keyword
HepatotoxicityOxidative stressThioacetamideVitamin D3 upregulated protein 1
ISSN
0041-008X
Publisher
Elsevier
DOI
http://dx.doi.org/10.1016/j.taap.2010.08.009
Type
Article
Appears in Collections:
Ochang Branch Institute > Division of Bioinfrastructure > Laboratory Animal Resource Center > 1. Journal Articles
Division of Biomedical Research > Immunotherapy Research Center > 1. Journal Articles
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