A Comprehensive Review of the Pharmacological Importance of Dietary Flavonoids as Hepatoprotective Agents

Table 3

Mechanism of action of various flavonoids as a result of in-vivo and in-vitro research studies.

Flavonoids	Liver injury	Mechanism of action	Conclusion	References
Quercetin	Cholestatic liver injury in rats	Increase ORAI-1 gene expression	Increased ORAI-1 gene-mediated SOCE leads to improved platelet function in the bile duct ligation model of cholestasis in rats	[46]
	t-BHP induced acute liver damage in mice	Scavenge free radical, increase in GSH, CAT, SOD, and decrease in serum enzyme markers i.e., ALT, AST	Through an increase in antioxidant activity, quercetin neutralizes free radicals and lowers oxidative stress	[47]
Hesperetin	Both ethanol and lipopolysaccharide-induced RAW264.7 cells and alcohol induce mouse liver	Enhance NLRP12 in two in vivo and in-vitro models which lowers inflammatory factors and prevents expression and phosphorylation of P65 proteins	Hesperetin stimulated NLRP12 through NF-κB to lessen inflammation and liver damage	[55]
(HD-16) hesperetin derivative	Carbon tetrachloride-induced liver fibrosis and liver inflammation	α-SMA, Col3α1, TIMP-1, and Col1α1 expression were inhibited in TGF-1-stimulated LX-2 cells, and activating the SIRT3/AMPK pathway also reduced carbon tetrachloride-induced liver inflammation and fibrosis	Hesperetin derivative-16 attenuated carbon tetrachloride-induced liver fibrosis and inflammation	[57]
Apigenin	D- galactosamine/LPS-induced liver injury	Decrease in ALT, and AST, and raised the activity of superoxide dismutase, glutathione reductase, catalase, as well as Nrf-2 and PPARγ protein expression, and decrease in hepatic TNF-α, and NF-κB expression	Apigenin may ameliorate D-GalN/LPS-induced liver injury in mice by increased Nrf-2-mediated antioxidative enzyme and modulate the PPARγ/NF-κB mediated expression	[40]
	Edifenphos- induced toxicity by modulating ROS- mediated mitochondrial dysfunction, oxidative stress, and caspase signal pathway in rat liver and kidney	Apigenin ameliorated the edifenphos-induced oxidative damage via antioxidant activity or by scavenging free radicals	Apigenin reduces oxidative stress-induced damage in the liver	[60]
Epicatechin	Acetaminophen-induced acute hepatic injury of mice	Inhibit TNF-α, IL-6, and IL-1, reduce the pathway of mitochondrial apoptosis, increase Bcl-2 to amplify the antiapoptotic response, and inhibit bax caspase-3	In mice, epicatechin improves the antiapoptotic effect while decreasing the acute liver injury brought on by APAP	[41]
	Hepatic sinusoidal obstruction syndrome by inhibiting liver inflammatory and oxidative injury	In rats, epicatechin increased Nrf-2 translocation and the production of its downstream antioxidant gene	At a dosage of 0.02–0.04 g/kg, epicatechin reduced hepatic sinusoidal syndrome by reducing hepatic inflammation and oxidative stress	[61]
Malvidin	Lipopolysaccharide-induced acute liver injury	Reduce oxidative damage by activating the Nrf2 signalling cascade, reduce inflammation through blocking proinflammatory cytokines and mediators as well as NLRP3 inflammasome activity resulting attenuate apoptosis, and autophagy	Malvidin attenuated hepatocyte apoptosis and autophagy via an upregulating Nrf2 signalling pathway	[39]
Genistein	D-galactosamine induced liver fibrosis/chronic liver damage in rats	Inhibit activation of reduced expression in α-SMA and deposition of collagen matrix and elevation in blood serum AST, ALT and leads to increased expression of hepatocellular Smad7. Which finally muffles the expression of smad/TGF-β1 signalling	Alterations in histopathology brought on by D-GlN are substantially prevented by genistein (5 mg/kg BW)	[64]
Daidzein	LPS-induced hepatotoxicity	Inhibit inflammation and oxidative stress by reducing the level of AST, ALT, IL-6 IL-1β, and TNF and also increase the level of SOD by upregulating and downregulating Keap-1	Daidzein was found effective to ameliorate oxidative stress and inflammation in LPS-induced hepatotoxicity	[65]
	Hepatocellular carcinoma	Reduce the expression of the cyclin D1/CDK4 axis and the cyclin A/CDK2 axis in the liver tissue via downregulation of Bcl-2, and suppressing the expression of Ki-67	The daidzein and chicory combination was found to be effective to treat hepatocarcinogenesis	[66]

SODS = superoxide dismutases; SOCE = store opening calcium channel; TGF-β1 = transforming growth factor Beta 1; GSH = glutathione; ALT = alanine transaminase; CAT = catalase; AST = aspartate transaminase; NF-κB = nuclear factor kappa B; SIRT3 = silent mating type information regulation 2 homolog 3; α-SMA = α smooth muscle actin; NLRP3 = nucleotide-binding domain(NOD)-like receptor protein 3; Bax = Bcl-2 associated X protein; Smad = mother decapentaplegic homolog; Nrf2 = nuclear factor erythroid 2-related factor2; APAP = acetaminophen; D-GlN = D-galactosamine; PPARγ = peroxisome proliferator-activated receptor gamma; IL-6 = interleukin; IL-1β = interleukin-1 beta; LPS = lipopolysaccharide; t-BHP = tert-butyl hydroperoxide; TNF-α = tumor necrosis factor-alpha; ROS = reactive oxygen species.