The role of vitamin D3 upregulated protein 1 in thioacetamide-induced mouse hepatotoxicity.
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.
Kwon
Hyo-Jung
HJ
Biomedical Mouse Resource Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk, Republic of Korea.
Lim
Jong-Hwan
JH
Han
Jong-Tak
JT
Lee
Sae-Bhom
SB
Yoon
Won-Kee
WK
Nam
Ki-Hoan
KH
Choi
In-Pyo
IP
Kim
Dae-Yong
DY
Won
Young-Suk
YS
Kim
Hyoung-Chin
HC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000473:pathology* / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011897:Random Allocation; D013853:Thioacetamide / Q000633:toxicity*; D013879:Thioredoxins / Q000235:genetics / Q000502:physiology*
D002352:Carrier Proteins; C445672:Txnip protein, mouse; D013853:Thioacetamide; D013879:Thioredoxins