Tryptanthrin Protects Hepatocytes against Oxidative Stress via Activation of the Extracellular Signal-Regulated Kinase/NF-E2-Related Factor 2 Pathway

Tryptanthrin [6,12-dihydro-6,12-dioxoindolo-(2,1-b)-quinazoline], originally isolated from Isatidis radix, has been characterized as having anti-microbial and anti-tumor activities. It is well-known that excess oxidative stress is one of the major factors causing cell damage in the liver. This study...

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Bibliographic Details
Published in:Biological & pharmaceutical bulletin 2014/10/01, Vol.37(10), pp.1633-1640
Main Authors: Moon, Soo Young, Lee, Ju-Hee, Choi, Hee Yoon, Cho, Il Je, Kim, Sang Chan, Kim, Young Woo
Format: Article
Language:eng ; jpn
Subjects:
Drugs, Chinese Herbal - pharmacology
Enzyme Activation - drug effects
Enzyme Activation - physiology
extracellular signal-regulated kinase
Hep G2 Cells
Hepatocytes - drug effects
Hepatocytes - metabolism
Humans
MAP Kinase Signaling System - drug effects
MAP Kinase Signaling System - physiology
mitochondria
NF-E2-Related Factor 2 - metabolism
nuclear factor erythroid 2-related factor 2 (Nrf2)
oxidative stress
Oxidative Stress - drug effects
Oxidative Stress - physiology
Quinazolines - pharmacology
tert-butyl hydroperoxide
tryptanthrin
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Summary:Tryptanthrin [6,12-dihydro-6,12-dioxoindolo-(2,1-b)-quinazoline], originally isolated from Isatidis radix, has been characterized as having anti-microbial and anti-tumor activities. It is well-known that excess oxidative stress is one of the major factors causing cell damage in the liver. This study investigated the cytoprotective effects and molecular mechanism of tryptanthrin against tert-butyl hydroperoxide (tBHP)-induced oxidative stress in human hepatocyte-derived HepG2 cells. Tryptanthrin pre-treatment blocked the reactive oxygen species production, mitochondrial dysfunction, and cell death induced by tBHP. Moreover, tryptanthrin reversed tBHP-induced GSH reduction. This study also confirmed the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) by tryptanthrin as a plausible molecular mechanism for its cytoprotective effects. Specifically, tryptanthrin treatment induced nuclear translocation and transactivation of Nrf2 as well as phosphorylation of extracellular signal-regulated kinase (ERK), a potential upstream kinase of Nrf2. Tryptanthrin also up-regulated the expression of the heme oxygenase 1 and glutamate–cysteine ligase catalytic subunits, which are representative target genes of Nrf2. Moreover, inhibitor of ERK was used to verify the important role of the ERK-Nrf2 pathway in the hepatoprotective effects of tryptanthrin. In conclusion, this study demonstrated that tryptanthrin protects hepatocytes against oxidative stress through the activation of the ERK/Nrf2 pathway in HepG2 cells.
ISSN:0918-6158
1347-5215
DOI:10.1248/bpb.b14-00363