Possible involvement of Nrf2 and PPARγ up-regulation in the protective effect of umbelliferone against cyclophosphamide-induced hepatotoxicity

• Published in: Biomedicine & pharmacotherapy Vol. 86; pp. 297 - 306
• Main Authors: Mahmoud, Ayman M, Germoush, Mousa O, Alotaibi, Mohammed F, Hussein, Omnia E
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.02.2017
• Subjects: 7-Hydroxycoumarin; Animals; Cyclophosphamide; Cyclophosphamide - toxicity; Dose-Response Relationship, Drug; Hepatotoxicity; Internal Medicine; Liver - drug effects; Liver - metabolism; Liver - pathology; Male; Medical Education; NF-E2-Related Factor 2 - antagonists & inhibitors; NF-E2-Related Factor 2 - biosynthesis; Nrf2; Oxidative stress; PPAR gamma - antagonists & inhibitors; PPAR gamma - biosynthesis; PPARγ; Protective Agents - pharmacology; Random Allocation; Rats; Rats, Wistar; Umbelliferones - pharmacology; Up-Regulation - drug effects; Up-Regulation - physiology; ALP; alanine aminotransferase; ALT; umbelliferone; MDA; NF-κB; IFN-γ; cyclophosphamide; iNOS; alkaline phosphatase; malondialdehyde; Hepatotoxicity; heme oxygenase 1; catalase; retinoid X receptor; PBS; nitric oxide; qRT-PCR; nuclear factor-kappa B; UMB; IL-1β; Kelch-like ECH2-associated protein; PPARγ; GPx; ARE; superoxide dismutase; ROS; CAT; peroxisome proliferator activated receptor gamma; nuclear factor erythroid 2-related factor 2; glutathione peroxidase; NO; Oxidative stress; Reactive oxygen species; Keap 1; HO-1; RXR; interleukin-1beta; inducible nitric oxide synthase; reduced glutathione; tumor necrosis factor alpha; Nrf2; ANOVA; GSH; interferon-gamma; antioxidant response element; one-way analysis of variance; AST; SOD; CP; aspartate aminotransferase; TNF-α; phosphate buffered saline; 7-Hydroxycoumarin; quantitative reverse transcription-polymerase chain reaction; Cyclophosphamide
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2016.12.047

Abstract Umbelliferone (UMB) is a coumarin derivative with promising hepatoprotective effects. In this study, we examined the possible protective effects of UMB against cyclophosphamide (CP)-induced hepatotoxicity, addressing the question of the possible role of nuclear factor erythroid 2-related factor 2 (Nrf2) and peroxisome proliferator activated receptor gamma (PPARγ). Wistar rats were orally administered UMB at doses 50 and 100 mg/kg two weeks prior to CP injection. Five days after CP administration, the rats were sacrificed and samples were collected for analyses. CP induced a significant increase in circulating liver marker enzymes and pro-inflammatory cytokines. Hepatic lipid peroxidation and nitric oxide levels, and nuclear factor-kappaB (NF-κB) and inducible nitric oxide synthase (iNOS) expression were significantly increased following CP administration. UMB supplementation attenuated CP-induced inflammation and oxidative stress as assessed by restoration of the activity and expression of the antioxidant defenses, and suppression of pro-inflammatory cytokines. Histological examination also showed that UMB could significantly reduce CP-induced alterations. CP-induced rats showed significant down-regulation of Nrf2, HO-1 and PPARγ, an effect that was markedly reversed by UMB. In conclusion, the hepatoprotective effects of UMB appear to depend on co-activation of PPARγ and Nrf2, and subsequent suppression of oxidative stress and inflammation.