Table 1.
Various Nrf2 activator phytochemicals and their role in liver injury.
| Phytochemicals | Effective doses | Experimental procedure (injury model) | Outcomes | References |
|---|---|---|---|---|
| Acetaminophen toxicity | ||||
| Ginsenoside Rg3 | 3 μg/mL | Rat hepatocytes treated with 200 μM NAPQI | Repletion of GSH content and enhanced expression of Mrp expression | [39] |
| Oleanolic acid | 90 mg/kg | Mice injected with 330 μmol/kg APAP into the right femoral vein | Enhanced antioxidant response to reduce hepatocyte necrosis | [37] |
| Salvianolic acid B | 25 and 50 mg/kg | Mice treated with single dose of 300 mg/kg APAP (i.g.) | Antioxidant response and phase II enzyme induction via activation of PI3K/Akt and PKC signaling to reduce liver injury | [35] |
| Sauchinone | 30 mg/kg | Mice treated with single dose of 500 mg/kg APAP (i.p.) | Induction of antioxidant genes to reduce hepatocyte necrosis | [34] |
| Oleanolic acid | 5 mg/kg | Mice treated with single dose of 300 mg/kg APAP (i.p.) | Reduction of ROS generation, GSH depletion, and lipid peroxidation coupled with upregulation of antioxidant genes | [36] |
| Withaferin A | 40 mg/kg | Mice treated with single dose of 250 mg/kg APAP (i.p.) | Reduced hepatocyte injury by reducing GSH depletion | [38] |
|
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| Inflammatory injury | ||||
| Ellagic acid | 5, 10, and 20 mg/kg | Mice treated with single dose of 800 mg/kg Gal + 50 μg/kg LPS (i.p.) | Reduced LPS/GalN-induced NF-κB activation and increased antioxidant genes | [43] |
| Linalool | 10, 20, and 40 mg/kg | Mice treated with single dose of 800 mg/kg Gal + 50 μg/kg LPS (i.p.) | Reduced LPS/GalN-induced NF-κB activation and induction of cytoprotective genes | [44] |
| Mangiferin | 5, 10, and 20 mg/kg | Mice treated with single dose of 800 mg/kg Gal + 50 μg/kg LPS (i.p.) | Reduced liver injury by activating antioxidant pathway and inhibiting NLRP3 inflammasome activation | [45] |
| Oroxylin A | 15, 30, and 60 mg/kg | Mice treated with single dose of 800 mg/kg Gal + 50 μg/kg LPS (i.p.) | Decreased liver injury by activating antioxidant genes and inhibiting TLR4 signaling-mediated inflammation | [46] |
|
| ||||
| Chemical toxicity | ||||
| Tungtungmadic acid | 5 and 20 μM | Hepa1c1c7 cells treated with 250 μM t-BHP | HO-1 induction via the PI3K/Akt signaling pathway to reduce hepatocyte death | [47] |
| Antcin C | 20 μM in cells, 100 mg/kg in mice | HepG2 cells treated with 10 mM AAPH, mice treated with single dose of 80 mg/kg AAPH (i.p.) | Induction of antioxidant response via increase of JNK1/2 and PI3K/Akt activities | [48] |
| Butein and phloretin | 25 μM in vitro, 30 mg/kg in vivo | Mouse hepatocytes treated with 0.5 mM t-BHP, rats treated with single dose of 1 mL/kg CCl4 (i.p.) | Upregulation of HO-1 and GCLC expression through ERK2 pathway | [49] |
| Carthamus red | 10 and 20 mg/kg | Mice treated with two doses of 2 mL/kg CCl4-olive oil mixture (1 : 1) | Upregulation of Nrf2, GSTα, and NQO1 expressions associated with decreased hepatocyte injury and ALT levels | [50] |
| Curcumin | 200 mg/kg | Mice treated with single dose of 20 mg/kg DEN (i.p.) | Nrf2-mediated HO-1 induction and amelioration of hepatocyte injury | [51] |
| Diallyl disulfide | 50 and 100 mg/kg | Rats treated with single dose of 2 mL/kg CCl4 (i.g.) | Induction of antioxidant and detoxifying enzyme activities and suppressing of inflammatory cytokines production by reducing NF-κB activation | [52, 53] |
| Ginsenoside Rg1 | 20 and 40 mg/kg | Rats treated with 2 mL/kg of 50% CCl4 (s.c.) twice a week for 8 weeks | Reduced liver fibrosis by augmented antioxidant systems | [54] |
| Glycyrrhetinic acid | 25 and 50 mg/kg | Mice treated with 6.4 g/kg CCl4 (s.c.) for 30 days | Enhanced antioxidant genes expression to reduce hepatocyte injury | [55] |
| Hesperidin | 40 and 80 μM | LO-2 cells treated with 150 μM t-BHP | ERK-mediated nuclear translocation of Nrf2 to induce HO-1 gene expression and antioxidant response | [56] |
| Isoorientin | 5 μg/mL | HepG2 cells treated with 200 μM t-BHP | Upregulation of antioxidant enzyme expression through PI3K/Akt pathway | [57] |
| Naringenin | 50 mg/kg | Rats treated with 2 mL/kg CCl4-olive oil mixture (1 : 1) on days 2 and 5 (i.p.) | Increase in Nrf2 and HO-1 expression to reduce liver injury | [58] |
| Oxyresveratrol | 10 μM for in vitro study, 10 and 30 mg/kg for in vivo study | 200 μM t-BHP treatment to HepG2 cells, ice treated with single dose of 0.5 mL/kg CCl4 (i.p.) | ERK phosphorylation-mediated induction of antioxidant pathway to protect hepatocytes against oxidative stress, mitochondrial damage, and resultant cell death | [59] |
| Puerarin | 100 μM | 500 μM t-BHP treatment to Hepa1c1c7 and HepG2 cells | Augmentation of cellular antioxidant defenses through Nrf2-dependent HO-1 induction via PI3K pathway | [60] |
| Resveratrol | 50 and 75 μM | Primary rat hepatocytes treated with 500 μM t-BHP | Reduced hepatocyte death by improving antioxidant status | [61] |
| Schisandrin B | 15 μM | AML12 cells treated with 20 μM menadione for 1 h | Induction of ERK/Nrf2 signaling to enhance glutathione-mediated antioxidant response to protect hepatocytes against menadione-induced apoptosis | [62] |
|
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| Metal toxicity | ||||
| Curcumin | 200 mg/kg | Exposure of mice to NaAsO2 (100 mg/L) in drinking water | Induction of antioxidant genes and enhanced methylation and elimination of arsenic | [63] |
| Lutein | 40 mg/kg | Mice treated with 4 mg/kg As2O3 (i.g.) | Reduced liver injury by induction of antioxidant response | [64] |
| S-Allylcysteine | 100 mg/kg | Mice treated with single dose of 17 mg/kg K2Cr2O7 (s.c.) | Induction of antioxidant response to reduce liver injury | [65] |
|
| ||||
| Alcohol toxicity | ||||
| Lucidone | 1, 5, and 10 μg/mL | HepG2 cells treated with 100 mM ethanol | Induction of HO-1 via Nrf2 signaling pathway to enhance antioxidant response | [66] |
| Quercetin | 100 μM | Primary human hepatocytes treated with 100 mM ethanol | ERK- and p38-mediated Nrf2 nuclear translocation and subsequent induction of HO-1 activity | [67, 68] |
| Quercetin | 50 μM | LO-2 cells treated with 100 mM ethanol | Preventing hepatotoxicity by inducing p62 expression and induction of antioxidant response | [69] |
| Sulforaphane | 50 mg/kg | Mice treated with 3 g/kg ethanol (30%) for 5 days (i.g.) | Decreased hepatocyte lipid accumulation and injury without altering CYP2E1 expression | [70] |
|
| ||||
| Nonalcoholic steatohepatitis | ||||
| Baicalein | 10 mg/kg | Rats fed with MCD diet for 8 weeks | Reduction in inflammation and oxidative hepatocyte injury | [71] |
| Curcumin | 50 mg/kg | Rats fed with HFD for 6 weeks | Reduced hepatocyte lipid accumulation and improved insulin resistance and anti-inflammatory and antioxidant effects | [72] |
| Gastrodin | 10, 20, and 50 mg/kg | HL-7702 cells treated with 0.6 mM of OA for 24 h, mice fed with HFD for 10 weeks | AMPK-mediated induction of Nrf2 pathway to enhance expression of antioxidant enzymes | [73] |
| Lycopene | 15 mg/kg | Mice fed with HFD for the next 6 weeks following a single dose of 30 mg/kg DEN injection | Reduction in hepatocyte injury by induction of antioxidant pathway along with a decrease in CY2E1 expression | [74] |
|
| ||||
| Cholestatic liver injury | ||||
| Oleanolic acid | 20 mg/kg | Mice treated with 125 mg/kg LCA (i.p.) | Upregulation of Mrp2, Mrp3, and Mrp4 to reduce cholestatic liver injury | [75] |
| Oleanolic acid | 20 mg/kg | Bile duct ligation in mice | Induction of Mrps and FXR antagonism to reduce cholestatic liver injury | [76] |
| Paeoniflorin | 200 mg/kg | Rats treated with 50 mg/kg ANIT for 4 days (i.g.) | Enhanced GSH synthesis by activating Nrf2 through PI3K/Akt-dependent pathway | [8] |
| Sulforaphane | 50 mg/kg | Mice treated with 3 g/kg ethanol (30%) for 5 days (i.g.) | Decreased hepatocyte lipid accumulation and injury without altering CYP2E1 expression | [70] |
| Sulforaphane | 25 mg/kg | Bile duct ligation in mice | Antifibrotic response by inhibition of TGF-β/Smad signaling pathway | [77] |
AAPH: 2,2′-azobis(2-amidinopropane) dihydrochloride; MCD: methionine and choline deficient; CCl4: carbon tetrachloride; DEN: dimethylnitrosamine; HFD: high-fat diet; Gal: galactosamine; LPS: lipopolysaccharide; OA: oleic acid; NAPQI: N-acetylbenzoquinoneimine; i.p.: intraperitoneal; s.c.: subcutaneous; i.g.: intragastric; t-BHP: tert-butyl hydroperoxide; APAP: acetaminophen; LCA: lithocholic acid; ANIT: alpha-naphthylisothiocyanate; Nrf2: nuclear factor (erythroid-derived 2)-like 2; JNK1/2: c-Jun N-terminal kinases 1/2; PI3K/AKT: phosphoinositide 3-kinase/protein kinase B; HO-1: heme oxygenase-1; GCLC: glutamate-cysteine ligase catalytic subunit; ALT: alanine transaminase; GST: glutathione S-transferase; NQO1: NAD(P)H quinone dehydrogenase 1; AMPK: 5′ AMP-activated protein kinase; GSH: glutathione; CYP2E1: cytochrome P450 2E1; NLRP3: NLR family pyrin domain containing 3; Mrp: multidrug resistance-associated protein; TLR4: Toll-like receptor 4; Keap1: Kelch-like ECH-associated protein 1.