Activation of the Nrf2 Signaling Pathway Involving KLF9 Plays a Critical Role in Allicin Resisting Against Arsenic Trioxide-Induced Hepatotoxicity in Rats.

Abstract

Arsenic trioxide (As2O3) is both the most prevalent, naturally occurring inorganic arsenical threatening human health and an efficient therapeutic for acute promyelocytic leukemia. Regretfully, As2O3-treated cancer patients often suffer from hepatotoxicity. While effective antioxidant and anticarcinogenic actions of allicin have previously been demonstrated, studies indicating how allicin affects As2O3-induced hepatotoxicity and arsenic accumulation are lacking. Our study, for the first time, elaborates potential details of the hepatoprotective mechanisms of allicin against As2O3-induced liver injury. Wistar rats were administrated allicin (30 mg/kg) 1 h before As2O3 (3 mg/kg) by daily gavage for 2 weeks. Our results indicate that allicin ameliorated As2O3-induced liver dysfunction, oxidative stress, and arsenic accumulation in the liver. Meanwhile, allicin decreased NF-κB level and upregulated expression of proteins reduced by As2O3 including nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1, nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1, and Krüppel-like factor 9 (KLF9). In addition, allicin promoted B cell lymphoma-extra large expression and suppressed B cell lymphoma-2-associated X protein levels regulated by As2O3. However, neither allicin nor As2O3 affected cytochrome P450 2E1 mRNA expression. In conclusion, allicin attenuated As2O3-induced hepatotoxicity by activating the Nrf2 signaling pathway involving KLF9 to inhibit oxidative stress and apoptosis. Our findings elucidate a detailed mechanism by which allicin provides protection against As2O3-induced liver injury and support its potential role as an adjunctive therapy for patients suffering from chronic arsenic exposure.

• Authors: Daqian Yang, Zhanjun Lv, Haili Zhang, Biying Liu, Huijie Jiang, Xiao Tan, Jingjing Lu, Ruiqi Baiyun, Zhigang Zhang
• Journal: Biological trace element research (Biol Trace Elem Res) Vol. 176 Issue 1 Pg. 192-200 (Mar 2017) ISSN: 1559-0720 [Electronic] United States
• PMID: 27561292 (Publication Type: Journal Article)

Chemical References

• Antioxidants
• Arsenicals
• Disulfides
• Kruppel-Like Transcription Factors
• NF-E2-Related Factor 2
• NF-kappa B
• Nfe2l2 protein, rat
• Oxides
• Sulfinic Acids
• bcl-2-Associated X Protein
• bcl-X Protein
• Klf9 protein, rat
• allicin
• Cytochrome P-450 CYP2E1
• Heme Oxygenase-1
• NAD(P)H Dehydrogenase (Quinone)
• NQO1 protein, rat
• Arsenic
• Arsenic Trioxide

Topics

• Animals
• Antioxidants (pharmacology)
• Arsenic (blood, metabolism)
• Arsenic Trioxide
• Arsenicals
• Blotting, Western
• Chemical and Drug Induced Liver Injury (etiology, metabolism, prevention & control)
• Cytochrome P-450 CYP2E1 (genetics, metabolism)
• Disulfides
• Gene Expression (drug effects)
• Heme Oxygenase-1 (metabolism)
• Kruppel-Like Transcription Factors (metabolism)
• Liver (drug effects, metabolism, pathology)
• Male
• NAD(P)H Dehydrogenase (Quinone) (metabolism)
• NF-E2-Related Factor 2 (metabolism)
• NF-kappa B (metabolism)
• Oxidative Stress (drug effects)
• Oxides (toxicity)
• Rats, Wistar
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects, physiology)
• Sulfinic Acids (pharmacology)
• bcl-2-Associated X Protein (metabolism)
• bcl-X Protein (metabolism)