Table 2.
Hepatatoprotective and Hepatotoxic Effects of Emodin and Its Derivatives.
| Main effect | Model | Cell line or species | Agent/dose/administration route | Mechanism | Reference | |
|---|---|---|---|---|---|---|
| Hepatoprotection | In vitro: ↓hepatic oxidative stress and inflammatory response | Hepatic reperfusion (H/R) injury | In vitro: male C57BL/6 primary hepatocytes | In vitro: aloin (C21H22O9)*; 20 μM (pretreatment), 4 h hypoxia | In vitro: ↓TLR4/MyD88/NF-κB signaling pathway to ↓apoptosis and ↓ROS | Du et al 78 |
| In vivo: ↓I/R-induced liver damage | Hepatic ischemia-reperfusion (H I/R) injury | In vivo: 30 male C57BL/6 mice (6 mice/group) pretreated then portal vein and hepatic artery clamped for 1 h; 6 h reperfusion then sacrificed | In vivo: aloin*; 10, 20, 40 mg/kg; i.p., 5 days pretreatment Optimum: 20 mg/kg ↓ALT, AST |
In vivo: ↓TLR4/MyD88/NF-κB signaling pathway to ↓oxidative stress (↑SOD, ↑GSH,↓MDA), ↓hepatocellular apoptosis (↓Bax, ↑Bcl-2), and ↓inflammation (↓IL-6, ↓TNF-α, ↑IL-10) | ||
| ↓Chemically-induced oxidative/liver damage | Arachidonic acid (AA)+iron induced hepatic oxidative stress | In vitro: hepatocytes | In vitro: emodin; 3-30 µM, 1 h pretreatment before AA + iron Optimum: 10 μM |
In vitro: YAP1 inactivation to ↓apoptosis, ↓ROS, and ↓mitochondria damage | Lee et al 47 | |
| Acetaminophen (APAP) induced liver damage | In vivo: C57BL/6 mice | In vivo: emodin in 40% polyethylene glycol (PEG); 10 and 30 mg/kg, pretreated daily/3 days. APAP; 500 mg/kg; gavage, sacrificed after 6 h ↓ALT, ALP, and total bilirubin |
In vivo: LKB1-AMPK pathway activation and Hippo signaling pathway inactivation to ↓apoptosis, ↓antioxidant gene expression, ↓ROS, and ↓mitochondria damage | |||
| In vitro: ↑apototsis | HCC | In vitro: SMMC-7721 | In vitro: emodin*; 0-200 µM, 0-48 h IC50 ≈ 50 µM, 48 h |
In vitro: ↓p-Akt (PI3K), ↑MAPK (↑p-ERK, ↑p-p38, mild ↓JNK) at 100 µM, 0-60 min, time dependent | Lin et al 19 | |
| In vivo: ↓tumorigenesis | In vivo: 15 male BALB/c nude mice (5 mice/group) subcutaneously injected with SMMC-7721 cells | In vivo: emodin*; 25 or 50 mg/kg; i.p., daily/2 wks after tumor volume of 75-100 mm3
No toxicity or body weight changes ↓ALT, AST, AKP, GGT, Cr and BUN |
In vivo: ↑apoptosis | |||
| Protective effect on liver injury and fibrosis | Carbon tetrachloride (CCl4)-induced liver fibrosis | 50 SD rats (10 mice/group) | Emodin in CMC; 0, 10, 20, or 40 mg/kg; subcutaneous injection, daily/12 weeks after 2 ml/kg 40% CCl4 in olive oil; subcutaneous injection, 2x week/12 weeks ↓ALT, AST, ALP, γ-GT |
↓TGF-β1 signaling and EMT (↓p-Smad2, p-Smad3, FN, vimentin, Snail2, twist-related protein 1, ZEB-1; ↑E-cadherin). ↓Inflammatory cell infiltration, ↓hyperplasia, and ↓collagen deposition*** | Liu et al 52 | |
| ↓Hepatic fibrosis (↓HSC activation) | Hepatic fibrosis | HSC-T6 (activated rat hepatic stellate cells) | Emodin; proliferation: 0-300 μM, 0-48 h; All other: 3, 10, 30 μM, 24 h Optimal: 30 μM |
↓TGF-β1 (↓TGF-β receptor I/II) to ↓HSC proliferation and activation (↓α-SMA), ↓MAPK (p38)/Smad4 signaling and EMT genes (↓collagen, ↓FN); Little effect on p-JNK or ERK1/2. | Wang et al 46 | |
| Protective and rescue effect against intrahepatic cholestasis | Up- or down- regulation of farnesoid X receptor (FXR) | In vitro: Normal human hepatocyte line L02 | In vitro: emodin; 0.02, 0.04, and 0.08 µg/ml, 24 h | ↑BSEP, ↑FXR1, and ↑FXR2 (in vitro: regardless of FXR up/down regulation ) • *** | Xiong, Ding et al. (2019)80 | |
| ANIT-induced cholestasis | In vivo: 21 female and 21 male SD rats (6 mice/group) | In vivo: emodin; 20, 40, 80 mg/kg in CMC; gavage, 7 days. ANIT; 50 mg/kg on day 5. Optimum: 40 mg/kg ↓ALT, AST, TBIL, DBIL, ALP, γ-GT, and TBA levels |
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| Protective effect on liver lipid metabolism; ameliorated induced hepatic steatosis (lipid accumulation) | FFAs induced lipid accumulation | In vitro: HepG2 (HCC); primary male SD rat hepatocytes | In vitro: emodin; 20,40, 80 μM, 0-24 h, cotreated with 1 mM FFAs | Modulated CaMKK–AMPK–mTOR–p70S6K–SREBP1 signaling pathway (↑p-AMPK,↓SREBP1, ↓fatty acid synthase, ↓p-mTOR, ↓p70S6K); ↓hepatic lipogenesis and ↑fatty acid oxidation*** | Wang, Li et al. (2017) 81 | |
| High-fat diet (HFD)-induced fatty liver | In vivo: 50 male SD rats (10/group) given chow or HFD for 12 weeks. Emodin administered on week 4. | In vivo: emodin in 0.5% CMC; 40, 80, and 160 mg/kg; gavage, 1x daily/8 weeks ↓TC, ALT, AST, ALP, γ-GT, total protein, LDL-c, and MDA |
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| AMPK activation | Normal mouse liver | In vitro: primary mouse hepatocytes | In vitro: emodin; 10 µM, 6 h after compound C (AMPK inhibitor) pretreatment; 5 µM, 30 min | In vitro: ↓bsep | Wang et al 65 | |
| Protective against intrahepatic cholestasis liver injury | (ANIT)-induced intrahepatic cholestasis | In vivo (2 models): (1) Male C57BL/6 mice (6-8 mice/4 groups) (2) Male C57BL/6 mice (6-9 mice/4 groups) |
In vivo: (1) Emodin; 150 mg/kg emodin; 10% PEG400 in 0.5% CMC; p.o., daily/7 days. ANIT in corn oil; 50 mg/kg; p.o., 1x on day 5. ↓ALT, ALP, total bilirubin, bile acids (2) Emodin; 30, 90, and 300 mg/kg; gavage, daily/4 or 14 days |
(1) In livers: ↓anti-oxidative expressions (HO-1, Gpx2, Gsta1/2, and Gadd45a); ↓hepatic inflammation (↓IL-1b, IL-6, IL-10, and a-SMA) via ↓NF-kB pathway; ↓neutrophil infiltration, ↓necrosis; little effect on BA accumulation (2) AMPK activation to ↓bsep (time dependent) in livers*** |
||
| ↓LPS induced hepatocyte apoptosis and inflammatory injury activation | LPS-triggered liver cell inflammatory injury model | In vitro: L02 cells and primary hepatocytes (isolated from 4 Wistar rats) | In vitro: emodin; 0-20 µM (cell viability);15 µM (all other) after LPS pretreatment; 5 ug/ml | ↓IL-1B, IL-6, and TNF-a | Xie et al 38 | |
| In vivo: 30 C57BL/6 mice (10 mice/group) | In vivo: emodin; 50 mg/kg; i.p., 12 h pretreatment. LPS; 40 ug/kg; sacrificed 24 h | ↑miR-145, ↓IRAK1, ↓NF-κB pathway | ||||
| Protective against apoptosis | Normal human liver | L02 | Emodin; 0-80 µM, 0-24 h IC50 ≈ 80 µM, 24 h |
Induced autophagy via ↓p-PI3K, ↓p-AKT and ↓p-mTOR (time dependent)*** | Zheng et al 43 | |
| Hepatotoxicity | Aggravated emodin-induced liver injury | Liver injury induced by high dose emodin | In vitro: human primary hepatocytes | In vitro: emodin*; IC50 = 80 µM, 48 h after CYP3A induction (72 h)/inhibition (24 h) or GSH depletion | CYP3A activation and GSH depletion; CYP3A inhibitor with emodin (protective against/rescues liver injury) | Jiang et al. (2018) 82 |
| In vivo: Male SD rats | #In vivo: emodin in 0.5% CMC; 200 mg/kg; gavage, 1x/4 days and 400 mg/kg on day 5 with either CYP3A inhibitor (50 mg/kg) or GSH inhibitor (700 mg/kg); ip, 2 h before last emodin administration | |||||
| ↑Apoptosis | Normal human liver | L02 | Emodin; 50 µM,48 h | Inhibition of mitochondiral respiratory chain complexes (OxPhos), ↑ROS, ↑mitochondrial damage | Lin et al 63 | |
| Liver oxidative damage/injury | Normal liver | 12 Male SD rats (6 rats/group) | Emodin; 150 mg/kg; gavage; daily/4 weeks | ↓Mitochondrial FA b-oxidation, CAC, and ↓OxPhos; ↑ROS and mitochondrial dysfunction/damage; ↓anti-oxidants | Zhang et al 62 | |
| ↑Apoptosis | Normal human liver | L02 | Emodin; 160 µM, 0-24 h | ↑Cleaved cas-3; ↓autophagy via ↓p-PI3K, ↓p-AKT and ↓p-mTOR (time dependent)*** | Zheng et al 43 | |
| Aggravated ANIT-induced cholestatic liver injury | ANIT-induced intrahepatic cholestasis | Male C57BL/6J mice (6–8/ 6 groups) | #Semen cassiae (emodin-containing herb) in saline; 3000 or 10 000mg/kg; p.o., 7 days. ANIT in corn oil; 50 mg/kg; on day 5. ↑total bilirubin, Bas | Bsep inhibition to ↑bile acid accumulation in livers; not due to ↑oxidative stress/inflammation. Activation of AMPK-Fxr crosstalk (↑p-AMPK and ↓FXR in livers). | Wang et al 65 | |
| Liver injury | Normal liver | 48 SD male rats (12/group) | Emodin in saline; 150, 500, 1500 mg/kg; daily/7 weeks # | Inhibition of FADH/NADPH transport to ↑mitochondrial apoptosis | Yang et al 61 | |
| Liver oxidative damage | HCC | In vitro: HepG2; normal human liver HL7702 cells | In vitro: aloe emodin*; 1,15 or 30 μM, 0-48 h | ***Multidrug resistance protein 2 (ABCC2/ MRP2) inhibition via ↑ROS to ↑mitochondrial dysfunction, autophagy, and mitochondrial mediated apoptosis | Liu et al 64 | |
| In vivo: 30 male and female kunming mice (10 mice/group) | In vivo: aloe emodin in 0.5% CMC; 800 or 1600 mg/kg; intragastric, 11 weeks # | |||||
Abbreviations: CMC, sodium carboxymethylcellulose; HO-1, heme oxygenase-1; Gpx2, glutathione peroxidase 2, Gsta1/2: glutathione S-transferases, Gadd45a, growth arrest and DNA-damage-inducible protein.
*
Agent dissolved in DMSO.
**
Improved liver and kidney function (↓ ALT, AST, AKP, GGT, Cr and BUN).
***
Dose-dependent manner.
•More effective than ursodeoxycholic acid (UDCA: anti-cholestasis drug) and dexamethasone (DXM: immunosuppresspressive agent).
#↑ALT, AST.
↓TC, alanine transaminase, aspartate transaminase, alkaline phosphatase, γ-glutamyltransferase, total protein, LDL-c, and MDA.