Hepatoprotective actions of melatonin: Possible mediation by melatonin receptors

World Journal of Gastroenterology

Volumn 16, Issue 48, 2010, Pages 6087-6097

  Mathes, Alexander M ^a  

^a SAARLAND UNIVERSITY   (Germany)

Author keywords

Antioxidant enzymes; Hemorrhagic shock; Hepatoprotection; Ischemia; Liver; Liver function; Melatonin; Melatonin receptor; Ramelteon; Reperfusion; Sepsis; Toxic liver injury

Indexed keywords

ADENYLATE CYCLASE; ALKALINE PHOSPHATASE; ASPARTATE AMINOTRANSFERASE; BILIRUBIN; CALCIUM CHANNEL; CYCLIC AMP; CYTOKINE; GAMMA GLUTAMYLTRANSFERASE; GLUTATHIONE; GLUTATHIONE PEROXIDASE; GLUTATHIONE REDUCTASE; HEAT SHOCK PROTEIN; HYDROXYL RADICAL; LACTATE DEHYDROGENASE; MELATONIN; MELATONIN 1 RECEPTOR; MELATONIN 2 RECEPTOR; MELATONIN 3 RECEPTOR; MELATONIN RECEPTOR; NITRIC OXIDE; PEROXYNITRITE; PHOSPHOLIPASE A2; PHOSPHOLIPASE C; POTASSIUM CHANNEL; SUPEROXIDE; SUPEROXIDE DISMUTASE; UNCLASSIFIED DRUG;

ANTIOXIDANT ACTIVITY; DNA DEGRADATION; DRUG MECHANISM; GENE EXPRESSION; HEMORRHAGIC SHOCK; HUMAN; LIPID PEROXIDATION; LIVER CELL CARCINOMA; LIVER ISCHEMIA; LIVER PROTECTION; NONHUMAN; OXIDATIVE STRESS; PROTEIN DEGRADATION; PROTEIN EXPRESSION; REPERFUSION INJURY; RESUSCITATION; REVIEW; SEPSIS; SIGNAL TRANSDUCTION; SURVIVAL;

EID: 78650782788     PISSN: 10079327     EISSN: None     Source Type: Journal    
DOI: 10.3748/wjg.v16.i48.6087     Document Type: Review

References (186)

1. Reiter RJ, Tan DX, Manchester LC, Pilar Terron M, Flores LJ, Koppisepi S. Medical implications of melatonin: receptormediated and receptor-independent actions. Adv Med Sci 2007; 52: 11-28
2. Pandi-Perumal SR, Srinivasan V, Maestroni GJ, Cardinali DP, Poeggeler B, Hardeland R. Melatonin: Nature's most versatile biological signal? FEBS J 2006; 273: 2813-2838
3. Doolen S, Krause DN, Dubocovich ML, Duckles SP. Melatonin mediates two distinct responses in vascular smooth muscle. Eur J Pharmacol 1998; 345: 67-69
4. Ting KN, Dunn WR, Davies DJ, Sugden D, Delagrange P, Guardiola-Lemaître B, Scalbert E, Wilson VG. Studies on the vasoconstrictor action of melatonin and putative melatonin receptor ligands in the tail artery of juvenile Wistar rats. Br J Pharmacol 1997; 122: 1299-1306
5. Viswanathan M, Laitinen JT, Saavedra JM. Expression of melatonin receptors in arteries involved in thermoregulation. Proc Natl Acad Sci USA 1990; 87: 6200-6203
6. Arendt J. Melatonin and the pineal gland: influence on mammalian seasonal and circadian physiology. Rev Reprod 1998; 3: 13-22
7. Korf HW, Schomerus C, Stehle JH. The pineal organ, its hormone melatonin, and the photoneuroendocrine system. Adv Anat Embryol Cell Biol 1998; 146: 1-100
8. Klein DC, Moore RY. Pineal N-acetyltransferase and hydroxyindole-O-methyltransferase: control by the retinohypothalamic tract and the suprachiasmatic nucleus. Brain Res 1979; 174: 245-262
9. Reppert SM, Weaver DR. Coordination of circadian timing in mammals. Nature 2002; 418: 935-941
10. Sugden D. Melatonin biosynthesis in the mammalian pineal gland. Experientia 1989; 45: 922-932
11. Goldman BD. Mammalian photoperiodic system: formal properties and neuroendocrine mechanisms of photoperiodic time measurement. J Biol Rhythms 2001; 16: 283-301
12. Reiter RJ. The melatonin rhythm: both a clock and a calendar. Experientia 1993; 49: 654-664
13. Reiter RJ. The pineal and its hormones in the control of reproduction in mammals. Endocr Rev 1980; 1: 109-131
14. Lincoln GA, Andersson H, Hazlerigg D. Clock genes and the long-term regulation of prolactin secretion: evidence for a photoperiod/circannual timer in the pars tuberalis. J Neuroendocrinol 2003; 15: 390-397
15. Niklowitz P, Lerchl A, Nieschlag E. Photoperiodic responses in Djungarian hamsters (Phodopus sungorus): importance of light history for pineal and serum melatonin profiles. Biol Reprod 1994; 51: 714-724
16. Tosini G, Menaker M. The clock in the mouse retina: melatonin synthesis and photoreceptor degeneration. Brain Res 1998; 789: 221-228
17. Conti A, Conconi S, Hertens E, Skwarlo-Sonta K, Markowska M, Maestroni JM. Evidence for melatonin synthesis in mouse and human bone marrow cells. J Pineal Res 2000; 28: 193-202
18. Slominski A, Tobin DJ, Zmijewski MA, Wortsman J, Paus R. Melatonin in the skin: synthesis, metabolism and functions. Trends Endocrinol Metab 2008; 19: 17-24
19. Djeridane Y, Touitou Y. Melatonin synthesis in the rat harderian gland: age- and time-related effects. Exp Eye Res 2001; 72: 487-492
20. Champier J, Claustrat B, Besançon R, Eymin C, Killer C, Jouvet A, Chamba G, Fèvre-Montange M. Evidence for tryptophan hydroxylase and hydroxy-indol-O-methyl-transferase mRNAs in human blood platelets. Life Sci 1997; 60: 2191-2197
21. Carrillo-Vico A, Calvo JR, Abreu P, Lardone PJ, García-Mauriño S, Reiter RJ, Guerrero JM. Evidence of melatonin synthesis by human lymphocytes and its physiological significance: possible role as intracrine, autocrine, and/or paracrine substance. FASEB J 2004; 18: 537-539
22. Tijmes M, Pedraza R, Valladares L. Melatonin in the rat testis: evidence for local synthesis. Steroids 1996; 61: 65-68
23. Bubenik GA. Gastrointestinal melatonin: localization, function, and clinical relevance. Dig Dis Sci 2002; 47: 2336-2348
24. Stefulj J, Hörtner M, Ghosh M, Schauenstein K, Rinner I, Wölfler A, Semmler J, Liebmann PM. Gene expression of the key enzymes of melatonin synthesis in extrapineal tissues of the rat. J Pineal Res 2001; 30: 243-247
25. Reiter R, Tang L, Garcia JJ, Muñoz-Hoyos A. Pharmacological actions of melatonin in oxygen radical pathophysiology. Life Sci 1997; 60: 2255-2271
26. Cuzzocrea S, Reiter RJ. Pharmacological actions of melatonin in acute and chronic inflammation. Curr Top Med Chem 2002; 2: 153-165
27. Poeggeler B, Saarela S, Reiter RJ, Tan DX, Chen LD, Manchester LC, Barlow-Walden LR. Melatonin--a highly potent endogenous radical scavenger and electron donor: new aspects of the oxidation chemistry of this indole accessed in vitro. Ann N Y Acad Sci 1994; 738: 419-420
28. Hardeland R. Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance. Endocrine 2005; 27: 119-130
29. Tan DX, Manchester LC, Reiter RJ, Plummer BF, Hardies LJ, Weintraub ST, Vijayalaxmi, Shepherd AM. A novel melatonin metabolite, cyclic 3-hydroxymelatonin: a biomarker of in vivo hydroxyl radical generation. Biochem Biophys Res Commun 1998; 253: 614-620
30. Pieri C, Marra M, Moroni F, Recchioni R, Marcheselli F. Melatonin: a peroxyl radical scavenger more effective than vitamin E. Life Sci 1994; 55: PL271-PL276
31. Cagnoli CM, Atabay C, Kharlamova E, Manev H. Melatonin protects neurons from singlet oxygen-induced apoptosis. J Pineal Res 1995; 18: 222-226
32. Tan DX, Manchester LC, Burkhardt S, Sainz RM, Mayo JC, Kohen R, Shohami E, Huo YS, Hardeland R, Reiter RJ. N1- acetyl-N2-formyl-5-methoxykynuramine, a biogenic amine and melatonin metabolite, functions as a potent antioxidant. FASEB J 2001; 15: 2294-2296
33. Guenther AL, Schmidt SI, Laatsch H, Fotso S, Ness H, Ressmeyer AR, Poeggeler B, Hardeland R. Reactions of the melatonin metabolite AMK (N1-acetyl-5-methoxykynuramine) with reactive nitrogen species: formation of novel compounds, 3-acetamidomethyl-6-methoxycinnolinone and 3-nitro-AMK. J Pineal Res 2005; 39: 251-260
34. Tan DX, Manchester LC, Terron MP, Flores LJ, Reiter RJ. One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species? J Pineal Res 2007; 42: 28-42
35. Rodriguez C, Mayo JC, Sainz RM, Antolín I, Herrera F, Martín V, Reiter RJ. Regulation of antioxidant enzymes: a significant role for melatonin. J Pineal Res 2004; 36: 1-9
36. Tomás-Zapico C, Coto-Montes A. A proposed mechanism to explain the stimulatory effect of melatonin on antioxidative enzymes. J Pineal Res 2005; 39: 99-104
37. Bettahi I, Pozo D, Osuna C, Reiter RJ, Acuña-Castroviejo D, Guerrero JM. Melatonin reduces nitric oxide synthase activity in rat hypothalamus. J Pineal Res 1996; 20: 205-210
38. Pozo D, Reiter RJ, Calvo JR, Guerrero JM. Inhibition of cerebellar nitric oxide synthase and cyclic GMP production by melatonin via complex formation with calmodulin. J Cell Biochem 1997; 65: 430-442
39. Zhang H, Akbar M, Kim HY. Melatonin: an endogenous negative modulator of 12-lipoxygenation in the rat pineal gland. Biochem J 1999; 344 Pt 2: 487-493
40. Crespo E, Macías M, Pozo D, Escames G, Martín M, Vives F, Guerrero JM, Acuña-Castroviejo D. Melatonin inhibits expression of the inducible NO synthase II in liver and lung and prevents endotoxemia in lipopolysaccharide-induced multiple organ dysfunction syndrome in rats. FASEB J 1999; 13: 1537-1546
41. Sener G, Toklu H, Kapucu C, Ercan F, Erkanli G, Kaçmaz A, Tilki M, Yeǧen BC. Melatonin protects against oxidative organ injury in a rat model of sepsis. Surg Today 2005; 35: 52-59
42. Carrillo-Vico A, Lardone PJ, Naji L, Fernández-Santos JM, Martín-Lacave I, Guerrero JM, Calvo JR. Beneficial pleiotropic actions of melatonin in an experimental model of septic shock in mice: regulation of pro-/anti-inflammatory cytokine network, protection against oxidative damage and anti-apoptotic effects. J Pineal Res 2005; 39: 400-408
43. Wu CC, Chiao CW, Hsiao G, Chen A, Yen MH. Melatonin prevents endotoxin-induced circulatory failure in rats. J Pineal Res 2001; 30: 147-156
44. Xu DX, Wei W, Sun MF, Wei LZ, Wang JP. Melatonin attenuates lipopolysaccharide-induced down-regulation of pregnane X receptor and its target gene CYP3A in mouse liver. J Pineal Res 2005; 38: 27-34
45. Sewerynek E, Abe M, Reiter RJ, Barlow-Walden LR, Chen L, McCabe TJ, Roman LJ, Diaz-Lopez B. Melatonin administration prevents lipopolysaccharide-induced oxidative damage in phenobarbital-treated animals. J Cell Biochem 1995; 58: 436-444
46. Sewerynek E, Melchiorri D, Reiter RJ, Ortiz GG, Lewinski A. Lipopolysaccharide-induced hepatotoxicity is inhibited by the antioxidant melatonin. Eur J Pharmacol 1995; 293: 327-334
47. Wang H, Wei W, Shen YX, Dong C, Zhang LL, Wang NP, Yue L, Xu SY. Protective effect of melatonin against liver injury in mice induced by Bacillus Calmette-Guerin plus lipopolysaccharide. World J Gastroenterol 2004; 10: 2690-2696
48. Wang H, Xu DX, Lv JW, Ning H, Wei W. Melatonin attenuates lipopolysaccharide (LPS)-induced apoptotic liver damage in D-galactosamine-sensitized mice. Toxicology 2007; 237: 49-57
49. Wu JY, Tsou MY, Chen TH, Chen SJ, Tsao CM, Wu CC. Therapeutic effects of melatonin on peritonitis-induced septic shock with multiple organ dysfunction syndrome in rats. J Pineal Res 2008; 45: 106-116
50. Mathes AM, Kubulus D, Pradarutti S, Bentley A, Weiler J, Wolf B, Ziegeler S, Bauer I, Rensing H. Melatonin pretreatment improves liver function and hepatic perfusion after hemorrhagic shock. Shock 2008; 29: 112-118
51. Mathes AM, Kubulus D, Weiler J, Bentley A, Waibel L, Wolf B, Bauer I, Rensing H. Melatonin receptors mediate improvements of liver function but not of hepatic perfusion and integrity after hemorrhagic shock in rats. Crit Care Med 2008; 36: 24-29
52. Yang FL, Subeq YM, Lee CJ, Lee RP, Peng TC, Hsu BG. Melatonin Ameliorates Hemorrhagic Shock-Induced Organ Damage in Rats. J Surg Res 2009; Epub ahead of print
53. Rodríguez-Reynoso S, Leal C, Portilla E, Olivares N, Muñiz J. Effect of exogenous melatonin on hepatic energetic status during ischemia/reperfusion: possible role of tumor necrosis factor-alpha and nitric oxide. J Surg Res 2001; 100: 141-149
54. Bülbüller N, Cetinkaya Z, Akkus MA, Cifter C, Ilhan YS, Dogru O, Aygen E. The effects of melatonin and prostaglandin E1 analogue on experimental hepatic ischaemia reperfusion damage. Int J Clin Pract 2003; 57: 857-860
55. Sener G, Tosun O, Sehirli AO, Kaçmaz A, Arbak S, Ersoy Y, Ayanoǧlu-Dülger G. Melatonin and N-acetylcysteine have beneficial effects during hepatic ischemia and reperfusion. Life Sci 2003; 72: 2707-2718
56. Zhang WH, Li JY, Zhou Y. Melatonin abates liver ischemia/ reperfusion injury by improving the balance between nitric oxide and endothelin. Hepatobiliary Pancreat Dis Int 2006; 5: 574-579
57. Park SW, Choi SM, Lee SM. Effect of melatonin on altered expression of vasoregulatory genes during hepatic ischemia/ reperfusion. Arch Pharm Res 2007; 30: 1619-1624
58. Sewerynek E, Reiter RJ, Melchiorri D, Ortiz GG, Lewinski A. Oxidative damage in the liver induced by ischemia-reperfusion: protection by melatonin. Hepatogastroenterology 1996; 43: 898-905
59. Kim SH, Lee SM. Cytoprotective effects of melatonin against necrosis and apoptosis induced by ischemia/reperfusion injury in rat liver. J Pineal Res 2008; 44: 165-171
60. Liang R, Nickkholgh A, Hoffmann K, Kern M, Schneider H, Sobirey M, Zorn M, Büchler MW, Schemmer P. Melatonin protects from hepatic reperfusion injury through inhibition of IKK and JNK pathways and modification of cell proliferation. J Pineal Res 2009; 46: 8-14
61. Baykara B, Tekmen I, Pekcetin C, Ulukus C, Tuncel P, Sagol O, Ormen M, Ozogul C. The protective effects of carnosine and melatonin in ischemia-reperfusion injury in the rat liver. Acta Histochem 2009; 111: 42-51
62. Li JY, Yin HZ, Gu X, Zhou Y, Zhang WH, Qin YM. Melatonin protects liver from intestine ischemia reperfusion injury in rats. World J Gastroenterol 2008; 14: 7392-7396
63. Kirimlioglu H, Ecevit A, Yilmaz S, Kirimlioglu V, Karabulut AB. Effect of resveratrol and melatonin on oxidative stress enzymes, regeneration, and hepatocyte ultrastructure in rats subjected to 70% partial hepatectomy. Transplant Proc 2008; 40: 285-289
64. Carneiro RC, Reiter RJ. Delta-aminolevulinic acid-induced lipid peroxidation in rat kidney and liver is attenuated by melatonin: an in vitro and in vivo study. J Pineal Res 1998; 24: 131-136
65. Karbownik M, Reiter RJ, Garcia JJ, Tan DX, Qi W, Manchester LC. Melatonin reduces rat hepatic macromolecular damage due to oxidative stress caused by delta-aminolevulinic acid. Biochim Biophys Acta 2000; 1523: 140-146
66. Matsura T, Nishida T, Togawa A, Horie S, Kusumoto C, Ohata S, Nakada J, Ishibe Y, Yamada K, Ohta Y. Mechanisms of protection by melatonin against acetaminophen-induced liver injury in mice. J Pineal Res 2006; 41: 211-219
67. Sener G, Sehirli AO, Ayanoǧlu-Dülger G. Protective effects of melatonin, vitamin E and N-acetylcysteine against acetaminophen toxicity in mice: a comparative study. J Pineal Res 2003; 35: 61-68
68. Kanno S, Tomizawa A, Hiura T, Osanai Y, Kakuta M, Kitajima Y, Koiwai K, Ohtake T, Ujibe M, Ishikawa M. Melatonin protects on toxicity by acetaminophen but not on pharmacological effects in mice. Biol Pharm Bull 2006; 29: 472-476
69. Catalá A, Zvara A, Puskás LG, Kitajka K. Melatonin-induced gene expression changes and its preventive effects on adriamycin- induced lipid peroxidation in rat liver. J Pineal Res 2007; 42: 43-49
70. Rapozzi V, Comelli M, Mavelli I, Sentjurc M, Schara M, Perissin L, Giraldi T. Melatonin and oxidative damage in mice liver induced by the prooxidant antitumor drug, adriamycin. In Vivo 1999; 13: 45-50
71. Othman AI, El-Missiry MA, Amer MA, Arafa M. Melatonin controls oxidative stress and modulates iron, ferritin, and transferrin levels in adriamycin treated rats. Life Sci 2008; 83: 563-568
72. Meki AR, Abdel-Ghaffar SK, El-Gibaly I. Aflatoxin B1 induces apoptosis in rat liver: protective effect of melatonin. Neuro Endocrinol Lett 2001; 22: 417-426
73. Meki AR, Esmail Eel-D, Hussein AA, Hassanein HM. Caspase-3 and heat shock protein-70 in rat liver treated with aflatoxin B1: effect of melatonin. Toxicon 2004; 43: 93-100
74. Gesing A, Karbownik-Lewinska M. Protective effects of melatonin and N-acetylserotonin on aflatoxin B1-induced lipid peroxidation in rats. Cell Biochem Funct 2008; 26: 314-319
75. Ozen H, Karaman M, Ciǧremiş Y, Tuzcu M, Ozcan K, Erdaǧ D. Effectiveness of melatonin on aflatoxicosis in chicks. Res Vet Sci 2009; 86: 485-489
76. Sirajudeen M, Gopi K, Tyagi JS, Moudgal RP, Mohan J, Singh R. Protective effects of melatonin in reduction of oxidative damage and immunosuppression induced by aflatoxin B(1)-contaminated diets in young chicks. Environ Toxicol 2009; Epub ahead of print
77. Sigala F, Theocharis S, Sigalas K, Markantonis-Kyroudis S, Papalabros E, Triantafyllou A, Kostopanagiotou G, Andreadou I. Therapeutic value of melatonin in an experimental model of liver injury and regeneration. J Pineal Res 2006; 40: 270-279
78. Pal S, Chatterjee AK. Possible beneficial effects of melatonin supplementation on arsenic-induced oxidative stress in Wistar rats. Drug Chem Toxicol 2006; 29: 423-433
79. Kim CY, Lee MJ, Lee SM, Lee WC, Kim JS. Effect of melatonin on cadmium-induced hepatotoxicity in male Sprague- Dawley rats. Tohoku J Exp Med 1998; 186: 205-213
80. Eybl V, Kotyzova D, Koutensky J. Comparative study of natural antioxidants - curcumin, resveratrol and melatonin - in cadmium-induced oxidative damage in mice. Toxicology 2006; 225: 150-156
81. Kara H, Cevik A, Konar V, Dayangac A, Servi K. Effects of selenium with vitamin E and melatonin on cadmium-induced oxidative damage in rat liver and kidneys. Biol Trace Elem Res 2008; 125: 236-244
82. El-Sokkary GH, Nafady AA, Shabash EH. Melatonin administration ameliorates cadmium-induced oxidative stress and morphological changes in the liver of rat. Ecotoxicol Environ Saf 2010; 73: 456-463
83. Ohta Y, Kongo M, Sasaki E, Nishida K, Ishiguro I. Therapeutic effect of melatonin on carbon tetrachloride-induced acute liver injury in rats. J Pineal Res 2000; 28: 119-126
84. Ohta Y, Kongo-Nishimura M, Matsura T, Yamada K, Kitagawa A, Kishikawa T. Melatonin prevents disruption of hepatic reactive oxygen species metabolism in rats treated with carbon tetrachloride. J Pineal Res 2004; 36: 10-17
85. Ohta Y, Kongo M, Sasaki E, Nishida K, Ishiguro I. Preventive effect of melatonin on the progression of carbon tetrachloride- induced acute liver injury in rats. Adv Exp Med Biol 1999; 467: 327-332
86. Kus I, Ogeturk M, Oner H, Sahin S, Yekeler H, Sarsilmaz M. Protective effects of melatonin against carbon tetrachlorideinduced hepatotoxicity in rats: a light microscopic and biochemical study. Cell Biochem Funct 2005; 23: 169-174
87. Zavodnik LB, Zavodnik IB, Lapshina EA, Belonovskaya EB, Martinchik DI, Kravchuk RI, Bryszewska M, Reiter RJ. Protective effects of melatonin against carbon tetrachloride hepatotoxicity in rats. Cell Biochem Funct 2005; 23: 353-359
88. Wang H, Wei W, Wang NP, Gui SY, Wu L, Sun WY, Xu SY. Melatonin ameliorates carbon tetrachloride-induced hepatic fibrogenesis in rats via inhibition of oxidative stress. Life Sci 2005; 77: 1902-1915
89. Noyan T, Kömüroǧlu U, Bayram I, Sekeroǧlu MR. Comparison of the effects of melatonin and pentoxifylline on carbon tetrachloride-induced liver toxicity in mice. Cell Biol Toxicol 2006; 22: 381-391
90. Ogeturk M, Kus I, Pekmez H, Yekeler H, Sahin S, Sarsilmaz M. Inhibition of carbon tetrachloride-mediated apoptosis and oxidative stress by melatonin in experimental liver fibrosis. Toxicol Ind Health 2008; 24: 201-208
91. Hong RT, Xu JM, Mei Q. Melatonin ameliorates experimental hepatic fibrosis induced by carbon tetrachloride in rats. World J Gastroenterol 2009; 15: 1452-1458
92. Shaker ME, Houssen ME, Abo-Hashem EM, Ibrahim TM. Comparison of vitamin E, L-carnitine and melatonin in ameliorating carbon tetrachloride and diabetes induced hepatic oxidative stress. J Physiol Biochem 2009; 65: 225-233
93. Manda K, Bhatia AL. Prophylactic action of melatonin against cyclophosphamide-induced oxidative stress in mice. Cell Biol Toxicol 2003; 19: 367-372
94. Kwak CS, Mun KC. The beneficial effect of melatonin for cyclosporine hepatotoxicity in rats. Transplant Proc 2000; 32: 2009-2010
95. Rezzani R, Buffoli B, Rodella L, Stacchiotti A, Bianchi R. Protective role of melatonin in cyclosporine A-induced oxidative stress in rat liver. Int Immunopharmacol 2005; 5: 1397-1405
96. Kurus M, Esrefoglu M, Sogutlu G, Atasever A. Melatonin prevents cyclosporine-induced hepatotoxicity in rats. Med Princ Pract 2009; 18: 407-410
97. El-Sokkary GH. Melatonin and vitamin C administration ameliorate diazepam-induced oxidative stress and cell proliferation in the liver of rats. Cell Prolif 2008; 41: 168-176
98. Tahan V, Ozaras R, Canbakan B, Uzun H, Aydin S, Yildirim B, Aytekin H, Ozbay G, Mert A, Senturk H. Melatonin reduces dimethylnitrosamine-induced liver fibrosis in rats. J Pineal Res 2004; 37: 78-84
99. Jung KH, Hong SW, Zheng HM, Lee DH, Hong SS. Melatonin downregulates nuclear erythroid 2-related factor 2 and nuclear factor-kappaB during prevention of oxidative liver injury in a dimethylnitrosamine model. J Pineal Res 2009; 47: 173-183
100. Zhang L, Wei W, Xu J, Min F, Wang L, Wang X, Cao S, Tan DX, Qi W, Reiter RJ. Inhibitory effect of melatonin on diquatinduced lipid peroxidation in vivo as assessed by the measurement of F2-isoprostanes. J Pineal Res 2006; 40: 326-331
101. Xu J, Sun S, Wei W, Fu J, Qi W, Manchester LC, Tan DX, Reiter RJ. Melatonin reduces mortality and oxidatively mediated hepatic and renal damage due to diquat treatment. J Pineal Res 2007; 42: 166-171
102. Oz E, Ilhan MN. Effects of melatonin in reducing the toxic effects of doxorubicin. Mol Cell Biochem 2006; 286: 11-15
103. Omurtag GZ, Tozan A, Sehirli AO, Sener G. Melatonin protects against endosulfan-induced oxidative tissue damage in rats. J Pineal Res 2008; 44: 432-438
104. Swierczynska-Machura D, Lewinski A, Sewerynek E. Melatonin effects on Schiff's base levels induced by iodide administration in rats. Neuro Endocrinol Lett 2004; 25: 70-74
105. Tang L, Reiter RJ, Li ZR, Ortiz GG, Yu BP, Garcia JJ. Melatonin reduces the increase in 8-hydroxy-deoxyguanosine levels in the brain and liver of kainic acid-treated rats. Mol Cell Biochem 1998; 178: 299-303
106. El-Missiry MA. Prophylactic effect of melatonin on leadinduced inhibition of heme biosynthesis and deterioration of antioxidant systems in male rats. J Biochem Mol Toxicol 2000; 14: 57-62
107. El-Sokkary GH, Abdel-Rahman GH, Kamel ES. Melatonin protects against lead-induced hepatic and renal toxicity in male rats. Toxicology 2005; 213: 25-33
108. Kurcer Z, Oǧuz E, Iraz M, Fadillioglu E, Baba F, Koksal M, Olmez E. Melatonin improves methanol intoxication-induced oxidative liver injury in rats. J Pineal Res 2007; 43: 42-49
109. Jahovic N, Cevik H, Sehirli AO, Yeǧen BC, Sener G. Melatonin prevents methotrexate-induced hepatorenal oxidative injury in rats. J Pineal Res 2003; 34: 282-287
110. Sener G, Sehirli AO, Ayanoglu-Dülger G. Melatonin protects against mercury(II)-induced oxidative tissue damage in rats. Pharmacol Toxicol 2003; 93: 290-296
111. Ohta Y, Kongo M, Sasaki E, Ishiguro I, Harada N. Protective effect of melatonin against alpha-naphthylisothiocyanateinduced liver injury in rats. J Pineal Res 2000; 29: 15-23
112. Ohta Y, Kongo M, Kishikawa T. Effect of melatonin on changes in hepatic antioxidant enzyme activities in rats treated with alpha-naphthylisothiocyanate. J Pineal Res 2001; 31: 370-377
113. Calvo JR, Reiter RJ, García JJ, Ortiz GG, Tan DX, Karbownik M. Characterization of the protective effects of melatonin and related indoles against alpha-naphthylisothiocyanateinduced liver injury in rats. J Cell Biochem 2001; 80: 461-470
114. Ohta Y, Kongo M, Kishikawa T. Preventive effect of melatonin on the progression of alpha-naphthylisothiocyanateinduced acute liver injury in rats. J Pineal Res 2003; 34: 185-193
115. Lankoff A, Banasik A, Nowak M. Protective effect of melatonin against nodularin-induced oxidative stress. Arch Toxicol 2002; 76: 158-165
116. Meki AR, Hussein AA. Melatonin reduces oxidative stress induced by ochratoxin A in rat liver and kidney. Comp Biochem Physiol C Toxicol Pharmacol 2001; 130: 305-313
117. Aydin G, Ozçelik N, Ciçek E, Soyöz M. Histopathologic changes in liver and renal tissues induced by Ochratoxin A and melatonin in rats. Hum Exp Toxicol 2003; 22: 383-391
118. Soyöz M, Ozçelik N, Kilinç I, Altuntaş I. The effects of ochratoxin A on lipid peroxidation and antioxidant enzymes: a protective role of melatonin. Cell Biol Toxicol 2004; 20: 213-219
119. Abdel-Wahhab MA, Abdel-Galil MM, El-Lithey M. Melatonin counteracts oxidative stress in rats fed an ochratoxin A contaminated diet. J Pineal Res 2005; 38: 130-135
120. Sutken E, Aral E, Ozdemir F, Uslu S, Alatas O, Colak O. Protective role of melatonin and coenzyme Q10 in ochratoxin A toxicity in rat liver and kidney. Int J Toxicol 2007; 26: 81-87
121. Melchiorri D, Reiter RJ, Attia AM, Hara M, Burgos A, Nistico G. Potent protective effect of melatonin on in vivo paraquatinduced oxidative damage in rats. Life Sci 1995; 56: 83-89
122. Melchiorri D, Reiter RJ, Sewerynek E, Hara M, Chen L, Nisticò G. Paraquat toxicity and oxidative damage. Reduction by melatonin. Biochem Pharmacol 1996; 51: 1095-1099
123. Hsu C, Han B, Liu M, Yeh C, Casida JE. Phosphine-induced oxidative damage in rats: attenuation by melatonin. Free Radic Biol Med 2000; 28: 636-642
124. Tan DX, Pöeggeler B, Reiter RJ, Chen LD, Chen S, Manchester LC, Barlow-Walden LR. The pineal hormone melatonin inhibits DNA-adduct formation induced by the chemical carcinogen safrole in vivo. Cancer Lett 1993; 70: 65-71
125. Bruck R, Aeed H, Avni Y, Shirin H, Matas Z, Shahmurov M, Avinoach I, Zozulya G, Weizman N, Hochman A. Melatonin inhibits nuclear factor kappa B activation and oxidative stress and protects against thioacetamide induced liver damage in rats. J Hepatol 2004; 40: 86-93
126. Túnez I, Muñoz MC, Villavicencio MA, Medina FJ, de Prado EP, Espejo I, Barcos M, Salcedo M, Feijóo M, Montilla P. Hepato- and neurotoxicity induced by thioacetamide: protective effects of melatonin and dimethylsulfoxide. Pharmacol Res 2005; 52: 223-228
127. Túnez I, Muñoz MC, Medina FJ, Salcedo M, Feijóo M, Montilla P. Comparison of melatonin, vitamin E and L-carnitine in the treatment of neuro- and hepatotoxicity induced by thioacetamide. Cell Biochem Funct 2007; 25: 119-127
128. Cuzzocrea S, Zingarelli B, Costantino G, Caputi AP. Protective effect of melatonin in a non-septic shock model induced by zymosan in the rat. J Pineal Res 1998; 25: 24-33
129. El-Sokkary GH, Reiter RJ, Cuzzocrea S, Caputi AP, Hassanein AF, Tan DX. Role of melatonin in reduction of lipid peroxidation and peroxynitrite formation in non-septic shock induced by zymosan. Shock 1999; 12: 402-408
130. López PM, Fiñana IT, De Agueda MC, Sánchez EC, Muñoz MC, Alvarez JP, De La Torre Lozano EJ. Protective effect of melatonin against oxidative stress induced by ligature of extra-hepatic biliary duct in rats: comparison with the effect of S-adenosyl-L-methionine. J Pineal Res 2000; 28: 143-149
131. Montilla P, Cruz A, Padillo FJ, Túnez I, Gascon F, Muñoz MC, Gómez M, Pera C. Melatonin versus vitamin E as protective treatment against oxidative stress after extra-hepatic bile duct ligation in rats. J Pineal Res 2001; 31: 138-144
132. Ohta Y, Kongo M, Kishikawa T. Melatonin exerts a therapeutic effect on cholestatic liver injury in rats with bile duct ligation. J Pineal Res 2003; 34: 119-126
133. Bülbüller N, Akkuş MA, Cetinkaya Z, Ilhan YS, Ozercan I, Kirkil C, Doǧru O. Effects of melatonin and lactulose on the liver and kidneys in rats with obstructive jaundice. Pediatr Surg Int 2002; 18: 677-680
134. Ohta Y, Kongo M, Kishikawa T. Therapeutic effect of melatonin on cholestatic liver injury in rats with bile duct ligation. Adv Exp Med Biol 2003; 527: 559-565
135. Padillo FJ, Cruz A, Navarrete C, Bujalance I, Briceño J, Gallardo JI, Marchal T, Caballero R, Túnez I, Muntané J, Montilla P, Pera-Madrazo C. Melatonin prevents oxidative stress and hepatocyte cell death induced by experimental cholestasis. Free Radic Res 2004; 38: 697-704
136. Esrefoglu M, Gül M, Emre MH, Polat A, Selimoglu MA. Protective effect of low dose of melatonin against cholestatic oxidative stress after common bile duct ligation in rats. World J Gastroenterol 2005; 11: 1951-1956
137. Ohta Y, Imai Y, Matsura T, Yamada K, Tokunaga K. Successively postadministered melatonin prevents disruption of hepatic antioxidant status in rats with bile duct ligation. J Pineal Res 2005; 39: 367-374
138. Muñoz-Castañeda JR, Túnez I, Herencia C, Ranchal I, González R, Ramírez LM, Arjona A, Barcos M, Espejo I, Cruz A, Montilla P, Padillo FJ, Muntané J. Melatonin exerts a more potent effect than S-adenosyl-l-methionine against iron metabolism disturbances, oxidative stress and tissue injury induced by obstructive jaundice in rats. Chem Biol Interact 2008; 174: 79-87
139. Emre MH, Polat A, Eşrefoǧlu M, Karabulut AB, Gül M. Effects of melatonin and acetylsalicylic acid against hepatic oxidative stress after bile duct ligation in rat. Acta Physiol Hung 2008; 95: 349-363
140. Huang LT, Tiao MM, Tain YL, Chen CC, Hsieh CS. Melatonin ameliorates bile duct ligation-induced systemic oxidative stress and spatial memory deficits in developing rats. Pediatr Res 2009; 65: 176-180
141. Karbownik M, Reiter RJ, Qi W, Garcia JJ, Tan DX, Manchester LC, Vijayalaxmi. Protective effects of melatonin against oxidation of guanine bases in DNA and decreased microsomal membrane fluidity in rat liver induced by whole body ionizing radiation. Mol Cell Biochem 2000; 211: 137-144
142. Taysi S, Koc M, Büyükokuroǧlu ME, Altinkaynak K, Sahin YN. Melatonin reduces lipid peroxidation and nitric oxide during irradiation-induced oxidative injury in the rat liver. J Pineal Res 2003; 34: 173-177
143. Sener G, Jahovic N, Tosun O, Atasoy BM, Yeǧen BC. Melatonin ameliorates ionizing radiation-induced oxidative organ damage in rats. Life Sci 2003; 74: 563-572
144. Koc M, Taysi S, Buyukokuroglu ME, Bakan N. Melatonin protects rat liver against irradiation-induced oxidative injury. J Radiat Res (Tokyo) 2003; 44: 211-215
145. El-Missiry MA, Fayed TA, El-Sawy MR, El-Sayed AA. Ameliorative effect of melatonin against gamma-irradiationinduced oxidative stress and tissue injury. Ecotoxicol Environ Saf 2007; 66: 278-286
146. El-Sokkary GH, Omar HM, Hassanein AF, Cuzzocrea S, Reiter RJ. Melatonin reduces oxidative damage and increases survival of mice infected with Schistosoma mansoni. Free Radic Biol Med 2002; 32: 319-332
147. Yan JJ, Shen F, Wang K, Wu MC. Patients with advanced primary hepatocellular carcinoma treated by melatonin and transcatheter arterial chemoembolization: a prospective study. Hepatobiliary Pancreat Dis Int 2002; 1: 183-186
148. Daniels WM, Reiter RJ, Melchiorri D, Sewerynek E, Pablos MI, Ortiz GG. Melatonin counteracts lipid peroxidation induced by carbon tetrachloride but does not restore glucose-6 phosphatase activity. J Pineal Res 1995; 19: 1-6
149. Kim SJ, Reiter RJ, Rouvier Garay MV, Qi W, El-Sokkary GH, Tan DX. 2-Nitropropane-induced lipid peroxidation: antitoxic effects of melatonin. Toxicology 1998; 130: 183-190
150. Genç S, Gürdöl F, Oner-Iyidoǧan Y, Onaran I. The effect of melatonin administration on ethanol-induced lipid peroxidation in rats. Pharmacol Res 1998; 37: 37-40
151. El-Sokkary GH, Reiter RJ, Tan DX, Kim SJ, Cabrera J. Inhibitory effect of melatonin on products of lipid peroxidation resulting from chronic ethanol administration. Alcohol Alcohol 1999; 34: 842-850
152. Hu S, Yin S, Jiang X, Huang D, Shen G. Melatonin protects against alcoholic liver injury by attenuating oxidative stress, inflammatory response, and apoptosis. Eur J Pharmacol 2009; 616: 287-292
153. Dubocovich ML, Rivera-Bermudez MA, Gerdin MJ, Masana MI. Molecular pharmacology, regulation and function of mammalian melatonin receptors. Front Biosci 2003; 8: d1093-d1108
154. Jockers R, Maurice P, Boutin JA, Delagrange P. Melatonin receptors, heterodimerization, signal transduction and binding sites: what's new? Br J Pharmacol 2008; 154: 1182-1195
155. von Gall C, Stehle JH, Weaver DR. Mammalian melatonin receptors: molecular biology and signal transduction. Cell Tissue Res 2002; 309: 151-162
156. New DC, Tsim ST, Wong YH. G protein-linked effector and second messenger systems involved in melatonin signal transduction. Neurosignals 2003; 12: 59-70
157. Pandi-Perumal SR, Trakht I, Srinivasan V, Spence DW, Maestroni GJ, Zisapel N, Cardinali DP. Physiological effects of melatonin: role of melatonin receptors and signal transduction pathways. Prog Neurobiol 2008; 85: 335-353
158. Barrett P, Morris M, Choi WS, Ross A, Morgan PJ. Melatonin receptors and signal transduction mechanisms. Biol Signals Recept 1999; 8: 6-14
159. Nosjean O, Ferro M, Coge F, Beauverger P, Henlin JM, Lefoulon F, Fauchere JL, Delagrange P, Canet E, Boutin JA. Identification of the melatonin-binding site MT3 as the quinone reductase 2. J Biol Chem 2000; 275: 31311-31317
160. Ebisawa T, Karne S, Lerner MR, Reppert SM. Expression cloning of a high-affinity melatonin receptor from Xenopus dermal melanophores. Proc Natl Acad Sci USA 1994; 91: 6133-6137
161. Ishii H, Tanaka N, Kobayashi M, Kato M, Sakuma Y. Gene structures, biochemical characterization and distribution of rat melatonin receptors. J Physiol Sci 2009; 59: 37-47
162. Sánchez-Hidalgo M, Guerrero Montávez JM, Carrascosa-Salmoral Mdel P, Naranjo Gutierrez Mdel C, Lardone PJ, de la Lastra Romero CA. Decreased MT1 and MT2 melatonin receptor expression in extrapineal tissues of the rat during physiological aging. J Pineal Res 2009; 46: 29-35
163. Sallinen P, Saarela S, Ilves M, Vakkuri O, Leppäluoto J. The expression of MT1 and MT2 melatonin receptor mRNA in several rat tissues. Life Sci 2005; 76: 1123-1134
164. Mühlbauer E, Gross E, Labucay K, Wolgast S, Peschke E. Loss of melatonin signalling and its impact on circadian rhythms in mouse organs regulating blood glucose. Eur J Pharmacol 2009; 606: 61-71
165. Naji L, Carrillo-Vico A, Guerrero JM, Calvo JR. Expression of membrane and nuclear melatonin receptors in mouse peripheral organs. Life Sci 2004; 74: 2227-2236
166. Park YJ, Park JG, Hiyakawa N, Lee YD, Kim SJ, Takemura A. Diurnal and circadian regulation of a melatonin receptor, MT1, in the golden rabbitfish, Siganus guttatus. Gen Comp Endocrinol 2007; 150: 253-262
167. Park YJ, Park JG, Kim SJ, Lee YD, Saydur Rahman M, Takemura A. Melatonin receptor of a reef fish with lunar-related rhythmicity: cloning and daily variations. J Pineal Res 2006; 41: 166-174
168. Sauzet S, Besseau L, Herrera Perez P, Covès D, Chatain B, Peyric E, Boeuf G, Muñoz-Cueto JA, Falcón J. Cloning and retinal expression of melatonin receptors in the European sea bass, Dicentrarchus labrax. Gen Comp Endocrinol 2008; 157: 186-195
169. Confente F, Rendón MC, Besseau L, Falcón J, Muñoz-Cueto JA. Melatonin receptors in a pleuronectiform species, Solea senegalensis: Cloning, tissue expression, day-night and seasonal variations. Gen Comp Endocrinol 2010; 167: 202-214
170. Nosjean O, Nicolas JP, Klupsch F, Delagrange P, Canet E, Boutin JA. Comparative pharmacological studies of melatonin receptors: MT1, MT2 and MT3/QR2. Tissue distribution of MT3/QR2. Biochem Pharmacol 2001; 61: 1369-1379
171. Paul P, Lahaye C, Delagrange P, Nicolas JP, Canet E, Boutin JA. Characterization of 2-[125I]iodomelatonin binding sites in Syrian hamster peripheral organs. J Pharmacol Exp Ther 1999; 290: 334-340
172. Poon AM, Choy EH, Pang SF. Modulation of blood glucose by melatonin: a direct action on melatonin receptors in mouse hepatocytes. Biol Signals Recept 2001; 10: 367-379
173. Mathes A, Ruf CGA, Reus E, Wolf B, Abend M, Rensing H. Endogene und exogene Exposition gegenüber Melatonin vermindert die Nachweisbarkeit hepatischer Melatoninrezeptoren vom Typ 1 nach hämorrhagischem Schock bei der Ratte. Anasth Intensivmed 2009; 50: A439-A440
174. Mathes AM, Kubulus D, Waibel L, Weiler J, Heymann P, Wolf B, Rensing H. Selective activation of melatonin receptors with ramelteon improves liver function and hepatic perfusion after hemorrhagic shock in rat. Crit Care Med 2008; 36: 2863-2870
175. Mathes AM, Wolf B, Rensing H. Melatonin receptor antagonist luzindole is a powerful radical scavenger in vitro. J Pineal Res 2008; 45: 337-338
176. Requintina PJ, Oxenkrug GF. Effect of luzindole and other melatonin receptor antagonists on iron- and lipopolysaccharide- induced lipid peroxidation in vitro. Ann N Y Acad Sci 2007; 1122: 289-294
177. Lochner A, Genade S, Davids A, Ytrehus K, Moolman JA. Short- and long-term effects of melatonin on myocardial postischemic recovery. J Pineal Res 2006; 40: 56-63
178. Rezzani R, Rodella LF, Bonomini F, Tengattini S, Bianchi R, Reiter RJ. Beneficial effects of melatonin in protecting against cyclosporine A-induced cardiotoxicity are receptor mediated. J Pineal Res 2006; 41: 288-295
179. Husson I, Mesplès B, Bac P, Vamecq J, Evrard P, Gressens P. Melatoninergic neuroprotection of the murine periventricular white matter against neonatal excitotoxic challenge. Ann Neurol 2002; 51: 82-92
180. Brzozowski T, Konturek PC, Zwirska-Korczala K, Konturek SJ, Brzozowska I, Drozdowicz D, Sliwowski Z, Pawlik M, Pawlik WW, Hahn EG. Importance of the pineal gland, endogenous prostaglandins and sensory nerves in the gastroprotective actions of central and peripheral melatonin against stress-induced damage. J Pineal Res 2005; 39: 375-385
181. Witt-Enderby PA, Radio NM, Doctor JS, Davis VL. Therapeutic treatments potentially mediated by melatonin receptors: potential clinical uses in the prevention of osteoporosis, cancer and as an adjuvant therapy. J Pineal Res 2006; 41: 297-305
182. Mathes A, Ruf C, Fink T, Abend M, Rensing H. Molecular effects of melatonin and ramelteon administration after hemorrhagic shock in rat liver: BAPCPC1-6. Eur J Anaesthesiol 2010; 27: 2
183. Schemmer P, Nickkholgh A, Schneider H, Sobirey M, Weigand M, Koch M, Weitz J, Büchler MW. PORTAL: pilot study on the safety and tolerance of preoperative melatonin application in patients undergoing major liver resection: a double-blind randomized placebo-controlled trial. BMC Surg 2008; 8: 2
184. Vairetti M, Ferrigno A, Bertone R, Rizzo V, Richelmi P, Bertè F, Reiter RJ, Freitas I. Exogenous melatonin enhances bile flow and ATP levels after cold storage and reperfusion in rat liver: implications for liver transplantation. J Pineal Res 2005; 38: 223-230
185. Freitas I, Bertone V, Guarnaschelli C, Ferrigno A, Boncompagni E, Rizzo V, Reiter RJ, Barni S, Vairetti M. In situ demonstration of improvement of liver mitochondria function by melatonin after cold ischemia. In Vivo 2006; 20: 229-237
186. Casillas-Ramírez A, Mosbah IB, Ramalho F, Roselló-Catafau J, Peralta C. Past and future approaches to ischemia-reperfusion lesion associated with liver transplantation. Life Sci 2006; 79: 1881-1894