Hepatoprotective actions of melatonin: Possible mediation by melatonin receptors

Table 1 Hepatoprotective effects of melatonin in different models of stress

Model	Induction/type	Melatonin treatment	Hepatoprotective effects of melatonin	Species	Ref.
Septic shock	CLP/LPS/LPS + BCG	0.25-60 mg/kg ip/iv/po 1-10 ×	hLPO↓, AST/ALT/GGT/ALP/BIL↓, hGSH/hGPx/hSOD/hCAT↑, hNEC↓, hPMN infiltration↓, hTNF-α/hIL-1/hNO↓, 72-h survival rate↑	Rats, mice	[40-49]
Hemorrhagic shock	90 min (MAP 35)/40%	10 mg/kg iv 1 dose	AST/ALT/LDH↓, liver function PDR-ICG↑, hepatic perfusion↑, hNEC↓	Rats	[50-52]
Ischemia/reperfusion	40-60 min ischemia/ischemia + resection	10-20 mg/kg ip/im 1-5 ×	hLPO↓, AST/ALT/LDH↓, hGSH↑, hNEC↓, hMPO↓, hPMN infiltration↓, hTNF-α/hCAS/hAPO/hiNOS↓, 7-d survival rate↑	Rats	[53-62]
Surgical trauma	70% hepatectomy	10 mg/kg per day ip for 7 d	hLPO↓, hGSH↑, histological alterations↓	Rats	[63]
Toxic liver injury	δ-Aminolevulinic acid	10 mg/kg per day ip 7-14 d	hLPO↓, hepatic DNA damage↓	Rats	[64,65]
	Acetaminophen	10-100 mg/kg ip/po/sc 1 ×	hLPO↓, AST/ALT↓, hGSH↑, hMPO↓, hNEC↓, 72-h survival rate↑	Mice	[66-68]
	Adriamycin	2-6 mg/kg ip/sc 1-7 ×	hLPO↓, hGSH/hGPx/hCAT↑, hHSP 40/60/70↓	Rats, mice	[69-71]
	Aflatoxins	5-40 mg/kg per day ig/ip for 3-8 wk	hLPO↓, hGSH/hGPx↑, hCAS/hNO↓, hHSP-70↓, hNEC↓	Rats, chicks	[72-76]
	Allyl alcohol	100 mg/kg ip 1 ×	hLPO↓, AST/ALT/LDH↓, hGSH↑, hNEC↓	Rats	[77]
	Arsenic	10 mg/kg ip for 5 d	hLPO↓, hGSH/hSOD/hCAT↑	Rats	[78]
	Cadmium	10-12 mg/kg per day ip/po for 3-15 d	hLPO↓, hGSH/hGPx↑, hNEC↓	Rats, mice	[79-82]
	Carbon tetrachloride	10-100 mg/kg ip/sc 1-30 ×	hLPO↓, AST/ALT/ALP/LDH/BIL↓, hGSH/hSOD/hCAT↑, hXO↓, hNO↓, hTNF-α/hIL-1b/hNF-κB↓, hNEC↓	Rats, mice	[77,83-92]
	Cyclophosphamide	100 μg/kg per day po for 15 d	hLPO↓, hGSH↑	Mice	[93]
	Cyclosporin A	715 μg/kg per day ip for 14 d	hLPO↓, AST/ALT/GGT↓, hNEC↓	Rats	[94-96]
	Diazepam	5 mg/kg per day sc for 30 d	hLPO↓, hSOD/hGSH↑	Rats	[97]
	Dimethylnitrosamine	50-100 mg/kg per day ip for 14 d	hLPO↓, AST/ALT/ALP/BIL↓, hSOD/hGSH/hGPx/hHO-1↑, hTNF-α/hIL-1b/hIL-6/hNF-κB↓	Rats	[98,99]
	Diquat	20 mg/kg ip 1 ×	ALT↓, hepatic content of F2-isoprostane↓, 24-h survival rate↑	Rats, mice	[100,101]
	Doxorubicin	10 mg/kg sc for 7 d	hLPO↓, GGT/LDH↓	Rats	[102]
	Endosulfan	10 mg/kg ip for 5 d	hLPO↓, AST/ALT/LDH↓, hGSH↑, hMPO↓, hTNF-α/IL-1b↓	Rats	[103]
	Iodine	1 mg/kg per day ip for 14 d	Hepatic content of Schiff‘s bases↓	Rats	[104]
	Kainic acid	4-10 mg/kg ip 1 ×	Hepatic DNA damage↓	Rats	[105]
	Lead	10-30 mg/kg per day ig for 7-30 d	hLPO↓, hGSH/hGPx/hSOD↑, hNEC↓	Rats	[106,107]
	Methanol	10 mg/kg ip 2 ×	hLPO↓, hGSH/hGPx/hSOD/hCAT↑, hMPO/hNO↓	Rats	[108]
	Methotrexate	10 mg/kg per day ip for 5 d	hLPO↓, hGSH↑, hNEC↓	Rats	[109]
	Mercury-(II)	10 mg/kg ip 2 ×	hLPO↓, hGSH↑, hMPO↓	Rats	[110]
	α-Naphthylisothiocyanate	10-100 mg/kg ip/po 1-4 ×	hLPO↓, AST/ALT/LDH/GGT/ALP/BIL↓, hSOD/hCAT↑, hMPO↓	Rats	[111-114]
	Nodularin	5-15 mg/kg per day ip for 7 d	hGPx/hSOD/hCAT↑	Mice	[115]
	Ochratoxin A	5-20 mg/kg ig/po 1-28 ×	hLPO↓, GGT/ALP↓, hGSH/hGPx/hSOD/hCAT↑, hNEC↓	Rats	[116-120]
	Paraquat	1-10 mg/kg ip 5-6 ×	hLPO↓, hGSH↑, LD50 of paraquat↑	Rats	[121,122]
	Phosphine	10 mg/kg ip 1 ×	hLPO↓, hGSH↑	Rats	[123]
	Safrole	0.1-0.2 mg/kg sc 2 ×	Hepatic DNA damage↓	Rats	[124]
	Thioacetamide	3 mg/kg ip 3-5 ×	hLPO↓, AST/ALT/LDH/ammonia↓, hGSH/hCAT↑, hiNOS/hNEC↓	Rats	[125-127]
	Zymosan	5-50 mg/kg ip 1-7 ×	hLPO/hMPO↓	Rats	[128,129]
Cholestasis	Bile-duct ligation	0.5-100 mg/kg per day ip/po for 7-13 d	hLPO↓, AST/ALT/GGT/ALP/BIL↓, hGSH/hGPx/hSOD/hCAT↑, hMPO↓, hNO↓, hNEC↓, iron disturbances↓	Rats	[130-140]
Ionizing radiation	Full-body; 0.8-6.0 Gray	5-50 mg/kg ip 1-5 ×	hLPO↓, AST/ALT/GGT↓, hGSH/hSOD/hGPx↑, hMPO/hNO↓, hepatic DNA damage↓	Rats	[141-145]
Malaria	Schistosoma mansoni	10 mg/kg per day ip for 30 d	hLPO↓, AST/ALT↓, hGSH/hSOD↑, 56-d survival rate↑	Mice	[146]

↑: Upregulation/increase/improvement; ↓: Downregulation/decrease/deterioration; ALT: Alanine transaminase; ALP: Alkaline phosphatase; AST: Aspartate transaminase; BCG: Bacillus Calmette-Guérin; BIL: Bilirubin; CLP: Cecal-ligation and puncture; GGT: γ glutamyl transferase; hAPO: Hepatic apoptosis; hCAT: Hepatic catalase; hCAS: Hepatic caspase; hGPx: Hepatic glutathione peroxidase; hGSH: Hepatic glutathione; hHSP: Hepatic heat shock protein; hHO-1: Hepatic heme oxygenase 1; hIL: Hepatic interleukin; hiNOS: Hepatic inducible nitric oxide synthase; hLPO: Hepatic lipid peroxidation; hMPO: Hepatic myeloperoxidase; hNEC: Hepatocellular necrosis; hNF-κB: Nuclear factor κ-light-chain-enhancer of activated B cells; hNO: Hepatic nitric oxide; hPMN: Hepatic polymorphonuclear granulocytes; hSOD: Hepatic superoxide dismutase; hTNF-α: Hepatic tumor necrosis factor α; hXO: Hepatic xanthine oxidase; ig: Intragastrically; im: Intramuscularly; ip: Intraperitoneally; iv: Intravenously; LD: Lethal dose; LDH: Lactate dehydrogenase; LPS: Lipopolysaccharide; MAP: Mean arterial pressure; PDR-ICG: Plasma disappearance rate of indocyanine green; po: Per os; sc: Subcutaneously.

Table 2 Melatonin receptors in the liver of various species

Species	MT1	MT2	MT3/QR2	Technique	Ref.
Wistar rat	+	+	NT	RT-PCR	[161,162]
CH3/He mouse	+	+	NT	RT-PCR	[163]
Swiss mouse	+	-	NT	RT-PCR	[164]
Sprague-Dawley rat	-	+	NT	RT-PCR	[165]
Golden rabbitfish	+	+	NT	RT-PCR	[166,167]
European sea bass	-	+	NT	RT-PCR	[168]
Senegalese sole	+	-	NT	RT-PCR	[169]
Syrian hamster	NT	NT	+	Iodine ligand	[170,171]
CD-1 mouse	NT	NT	+	Iodine ligand	[170]
Dog	NT	NT	+	Iodine ligand	[170]
Cynomolgus monkey	NT	NT	+	Iodine ligand	[170]

+: Detected; -: Not detected; MT1: Melatonin receptor type 1; MT2: Melatonin receptor type 2; MT3/QR2: Melatonin receptor type 3/quinone reductase-2; NT: Not tested; RT-PCR: Reverse transcription-polymerase chain reaction.