Nutr Res Pract.  2019 Dec;13(6):473-479. 10.4162/nrp.2019.13.6.473.

Luteolin and luteolin-7-O-glucoside protect against acute liver injury through regulation of inflammatory mediators and antioxidative enzymes in GalN/LPS-induced hepatitic ICR mice

• Park CM
• Song YS

• KMID: 2464126
• DOI: http://doi.org/10.4162/nrp.2019.13.6.473

Abstract

BACKGROUND/OBJECTIVES
Anti-inflammatory and antioxidative activities of luteolin and luteolin-7-O-glucoside were compared in galactosamine (GalN)/lipopolysaccharide (LPS)-induced hepatitic ICR mice.
MATERIALS/METHODS
Male ICR mice (6 weeks old) were divided into 4 groups: normal control, GalN/LPS, luteolin, and luteolin-7-O-glucoside groups. The latter two groups were administered luteolin or luteolin-7-O-glucoside (50 mg/kg BW) daily by gavage for 3 weeks after which hepatitis was induced by intraperitoneal injection of GalN and LPS (1 g/kg BW and 10 µg/kg BW, respectively).
RESULTS
GalN/LPS produced acute hepatic injury by a sharp increase in serum AST, ALT, and TNF-α levels, increases that were ameliorated in the experimental groups. In addition, markedly increased expressions of cyclooxygenase (COX)-2 and its transcription factors, nuclear factor (NF)-κB and activator protein (AP)-1, were also significantly attenuated in the experimental groups. Compared to luteolin-7-O-glucoside, luteolin more potently ameliorated the levels of inflammatory mediators. Phase II enzymes levels and NF-E2 p45-related factor (Nrf)-2 activation that were decreased by GalN/LPS were increased by luteolin and luteolin-7-O-glucoside administration. In addition, compared to luteolin, luteolin-7-O-glucoside acted as a more potent inducer of changes in phase II enzymes. Liver histopathology results were consistent with the mediator and enzyme results.
CONCLUSION
Luteolin and luteolin-7-O-glucoside protect against GalN/LPS-induced hepatotoxicity through the regulation of inflammatory mediators and phase II enzymes.

Keyword

Luteolin; Luteolin-7-O-glucoside; Inflammation; NF-kappa B; NF-E2-Related Factor 2

MeSH Terms

Animals
Galactosamine
Hepatitis
Humans
Inflammation
Injections, Intraperitoneal
Liver*
Luteolin*
Male
Mice
Mice, Inbred ICR*
NF-E2-Related Factor 2
NF-kappa B
Prostaglandin-Endoperoxide Synthases
Transcription Factors
Galactosamine
Luteolin
NF-E2-Related Factor 2
NF-kappa B
Prostaglandin-Endoperoxide Synthases
Transcription Factors

Figure

• 

  Fig. 1 Effect of luteolin and luteolin 7-O-glucoside on serum AST and ALT activity levels in GalN/LPS-intoxicated ICR mice. AST and ALT activities were attenuated in luteolin and luteolin-7-O-glucoside administered groups of GalN/LPS-intoxicated ICR mice. Values sharing the same superscript are not significantly different at P < 0.05 (Duncan's multiple-range test). Lut-7-G, luteolin-7-O-glucoside; GalN, galactosamine; AST, aspartate aminotransferase; ALT, alanine aminotransferase.

• 

  Fig. 2 Effect of luteolin and luteolin 7-O-glucoside on histopathological changes in liver of mice treated with GalN/LPS. Liver tissue sections were stained with hematoxylin and eosin. The arrows indicate inflammatory cell infiltration and the asterisks exhibit necrosis in the liver tissue of GalN/LPS-intoxicated mouse. Magnification, 200×; scale bar, 100 µm.

• 

  Fig. 3 Effect of luteolin and luteolin 7-O-glucoside on serum TNF-α concentration and COX-2 expression in GalN/LPS-intoxicated ICR mice. Serum TNF-α concentration (A) and COX-2 protein expression (B) were analyzed by ELISA assay and western blot analysis, respectively. The data are representative of three independent experiments. The relative induction of COX-2 protein expression was quantified by densitometry with actin used as an internal control. The data represent the mean ± standard deviation of triplicate experiments. Values sharing the same superscript are not significantly different at P <0.05 (Duncan's multiple-range test). Lut-7-G, luteolin-7-O-glucoside; TNF, tumor necrosis factor; GalN, galactosamine; LPS, lipopolysaccharide; COX, cyclooxygenase.

• 

  Fig. 4 Effect of luteolin and luteolin 7-O-glucoside on the phosphorylation status of the inflammatory transcription factors NFκB and AP-1 in GalN/LPS-intoxicated ICR mice. (A) The phosphorylated status of p65 and c-jun, subunits of NFκB and AP-1, were analyzed by western blot analysis. The data are representative of three independent experiments. (B) The relative induction of p65 and c-jun phosphorylation was quantified by densitometry with actin used as an internal control. The data represent the mean ± standard deviation of triplicate experiments. Values sharing the same superscript are not significantly different at P < 0.05 (Duncan's multiple-range test). Lut-7-G, luteolin-7-Oglucoside; GalN, galactosamine; LPS, lipopolysaccharide.

• 

  Fig. 5 Effect of luteolin and luteolin 7-O-glucoside on phase II enzymes and their transcription factor, Nrf2, in GalN/LPS-intoxicated ICR mice.( A) The phase II enzymes and Nrf2 expressions were analyzed by western blot analysis. The data are representative of three independent experiments. (B) The relative induction of protein expression was quantified by densitometry with actin used as an internal control. The data represent the mean ± standard deviation of triplicate experiments. Values sharing the same superscript are not significantly different at P < 0.05 (Duncan's multiple-range test). Lut-7-G, luteolin-7-O-glucoside; Nrf2, nuclear factor E2-related factor 2; GalN, galactosamine; LPS, lipopolysaccharide; HO-1, heme oxygenase-1; NQO, quinone oxidoreductase; SOD, superoxide dismutase; CAT, catalase.

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