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. 2022 Jul 27:2022:2710607.
doi: 10.1155/2022/2710607. eCollection 2022.

Rutin and Quercetin Counter Doxorubicin-Induced Liver Toxicity in Wistar Rats via Their Modulatory Effects on Inflammation, Oxidative Stress, Apoptosis, and Nrf2

Osama M Ahmed  1 , Mohammed H Elkomy  2 , Hanaa I Fahim  1 , Mohamed B Ashour  1 , Ibrahim A Naguib  3 , Badrah S Alghamdi  4   5 , Heba Uallah R Mahmoud  1 , Noha A Ahmed  1
Affiliations

Rutin and Quercetin Counter Doxorubicin-Induced Liver Toxicity in Wistar Rats via Their Modulatory Effects on Inflammation, Oxidative Stress, Apoptosis, and Nrf2

Osama M Ahmed et al. Oxid Med Cell Longev. .

Abstract

The presented study was performed to verify whether rutin and/or quercetin can inhibit liver injury induced by doxorubicin (DXR) in male Wistar rats. In this study, male Wistar rats were treated via the oral route with rutin and quercetin (50 mg/kg) either alone or in combination every other day for five weeks concomitant with receiving intraperitoneal DXR (2 mg/kg) two times a week for five successive weeks. Quercetin, rutin, and their combination significantly improved the deteriorated serum AST, ALT, and ALP activities and total bilirubin level, as well as albumin, AFP, and CA 19.9 levels in DXR-injected rats. Treatments of the DXR-injected group with quercetin and rutin prevented the elevation in liver lipid peroxidation and the reduction in superoxide dismutase, glutathione-S-transferase and glutathione peroxidase activities, and glutathione content. Treatments with quercetin and rutin significantly repressed the elevated expression of liver p53 and TNF-α and enhanced Nrf2 expression. Furthermore, the treatments significantly reduced DXR-induced liver histological changes. In conclusion, rutin and quercetin either alone or in combination may have potential preventive effects against DXR-induced hepatotoxicity through inhibiting oxidative stress, inflammation, and apoptosis as well as modulating the Nrf2 expression.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Scheme 1
Scheme 1
Schematic diagram of animal groups and employed experimental design.
Figure 1
Figure 1
Photomicrograph of liver section in an untreated rat indicating normal liver architecture composed of a central vein (CV) with thin walls and normal hepatocytes with narrow intercellular sinusoids (S) (H&E; ×400).
Figure 2
Figure 2
Photomicrographs of liver sections in rats injected with DXR indicating inflammation (IF) of hepatic capsule (a), cytoplasmic vacuolization (V) of subcapsular hepatocytes (a, b), clear cells of hepatocytes (CC) (b), apoptosis (AP) of hepatocytes (c, d), and karyomegally (K) of hepatocytic nuclei (c) (H&E; ×400).
Figure 3
Figure 3
Photomicrographs of liver sections in rats injected with DXR after supplementing with rutin indicating necrosis (NC) of spaoradic hepatocytes (a) and fatty change (F) of hepatocytes (b) (H&E; ×400).
Figure 4
Figure 4
Photomicrographs of liver sections in rats injected with DXR after supplementing with quercetin indicating nearly normal structure of liver tissue with no histological changes (a, b) and slight vacuolization (V) of hepatocytes (c) (H&E; ×400).
Figure 5
Figure 5
Photomicrographs of liver sections in rats injected with DXR after supplementing with a combination of quercetin and rutin indicating slight vacuolization (V) of hepatocytes (a) and almost normal structure of the liver tissue with no histological changes (b, c) (H&E; ×400).
Figure 6
Figure 6
Photomicrographs of immunohistochemical sections of liver for detection of p53 showing weak expression in normal rats (a), very strong staining expression (immunopositivity indicated by brownish color) in DXR administered rats (b), weak expression in DXR administered rats treated with rutin (c), and moderate expression in DXR administered rats treated with quercetin (d) and its combination with rutin (6e) (×100).
Figure 7
Figure 7
Photomicrographs of immunohistochemical sections of liver for detection of TNF-α showing weak expression of in normal rats (a), strong expression (immunopositivity indicated by brownish color) in DXR-injected rats (b), weak expression in DXR-injected rats treated with rutin (c) and quercetin (d), and negative expression in DXR-injected rats treated with mixture of rutin and quercetin (e) (×100).
Figure 8
Figure 8
Photomicrographs of immunohistochemical sections of liver for detection of Nrf2 showing weak expression of Nrf2 in normal rats (a), very weak expression in DXR-injected rats (b), strong expression (immunopositivity indicated by brownish color) in DXR-injected rats treated with rutin (c), mild expression (immunopositivity indicated by brownish color) in DXR-injected rats treated with quercetin (d), and very weak expression in DXR-injected rats treated with a mixture of rutin and quercetin (e) (×100).
Scheme 2
Scheme 2
Schematic figure showing the mechanisms of action of rutin and quercetin to counter DXR hepatotoxicity via oxidative stress, inflammation and apoptosis suppression and antioxidant defense mechanism promotion through the Nrf2 signaling pathway. DXR: doxorubicin; Keap1: Kelch-like ECH-associated protein 1; ARE: antioxidant response element; Nrf2: nuclear factor E2-related factor 2; ROS: reactive oxygen species; TNFR: tumor necrosis factor-α receptor.
See this image and copyright information in PMC

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