CDDO-Im protects from acetaminophen hepatotoxicity through induction of Nrf2-dependent genes

Journal Article · Wed Apr 01 00:00:00 EDT 2009 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2008.12.024· OSTI ID:21182773

Reisman, Scott A; Buckley, David B; Tanaka, Yuji ^[1]

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1. Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160-7417 (United States)

CDDO-Im is a synthetic triterpenoid recently shown to induce cytoprotective genes through the Nrf2-Keap1 pathway, an important mechanism for the induction of cytoprotective genes in response to oxidative stress. Upon oxidative or electrophilic insult, the transcription factor Nrf2 translocates to the nucleus, heterodimerizes with small Maf proteins, and binds to antioxidant response elements (AREs) in the upstream promoter regions of various cytoprotective genes. To further elucidate the hepatoprotective effects of CDDO-Im, wild-type and Nrf2-null mice were pretreated with CDDO-Im (1 mg/kg, i.p.) or vehicle (DMSO), and then administered acetaminophen (500 mg/kg, i.p.). Pretreatment of wild-type mice with CDDO-Im reduced liver injury caused by acetaminophen. In contrast, hepatoprotection by CDDO-Im was not observed in Nrf2-null mice. CDDO-Im increased Nrf2 protein expression and Nrf2-ARE binding in wild-type, but not Nrf2-null mice. Furthermore, CDDO-Im increased the mRNA expression of the Nrf2 target genes NAD(P)H: quinone oxidoreductase-1 (Nqo1); glutamate-cysteine ligase, catalytic subunit (Gclc); and heme-oxygenase-1 (Ho-1), in both a dose- and time-dependent manner. Conversely, CDDO-Im did not induce Nqo1, Gclc, and Ho-1 mRNA expression in Nrf2-null mice. Collectively, the present study shows that CDDO-Im pretreatment induces Nrf2-dependent cytoprotective genes and protects the liver from acetaminophen-induced hepatic injury.

• OSTI ID: 21182773
• Journal Information: Toxicology and Applied Pharmacology, Vol. 236, Issue 1; Other Information: DOI: 10.1016/j.taap.2008.12.024; PII: S0041-008X(09)00010-6; Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ALANINES
AMINOTRANSFERASES
ANTIOXIDANTS
BENZOQUINONES
CYSTEINE
DMSO
FIBROSARCOMAS
GENES
GLUTATHIONE
HEME
INJURIES
LIGASES
LIVER
MICE
NAD
OXIDATION
OXYGENASES
PROMOTERS
TIME DEPENDENCE
TRANSCRIPTION FACTORS