PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of wjgLink to Publisher's site
 
World J Gastroenterol. 2010 December 28; 16(48): 6087–6097.
Published online 2010 December 28. doi:  10.3748/wjg.v16.i48.6087
PMCID: PMC3012585

Hepatoprotective actions of melatonin: Possible mediation by melatonin receptors

Abstract

Melatonin, the hormone of darkness and messenger of the photoperiod, is also well known to exhibit strong direct and indirect antioxidant properties. Melatonin has previously been demonstrated to be a powerful organ protective substance in numerous models of injury; these beneficial effects have been attributed to the hormone’s intense radical scavenging capacity. The present report reviews the hepatoprotective potential of the pineal hormone in various models of oxidative stress in vivo, and summarizes the extensive literature showing that melatonin may be a suitable experimental substance to reduce liver damage after sepsis, hemorrhagic shock, ischemia/reperfusion, and in numerous models of toxic liver injury. Melatonin’s influence on hepatic antioxidant enzymes and other potentially relevant pathways, such as nitric oxide signaling, hepatic cytokine and heat shock protein expression, are evaluated. Based on recent literature demonstrating the functional relevance of melatonin receptor activation for hepatic organ protection, this article finally suggests that melatonin receptors could mediate the hepatoprotective actions of melatonin therapy.

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

INTRODUCTION

It has been suggested that the substance melatonin (5-methoxy-N-acetyltryptamine), discovered by Aaron Lerner in 1958, exists in almost every animal species, and possibly even in all plants[1,2]. Its physiological functions are said to be diverse; while melatonin may be involved in modifications of vasomotor tone[3,4] and thermoregulation[5], it is primarily known as the signal of darkness[6].

In vertebrates, melatonin is synthesized in the pineal gland and secreted during darkness as a hormonal message of the photoperiod[7]. The rhythm of melatonin synthesis is mainly driven by an oscillator which is situated in the hypothalamic suprachiasmatic nucleus (SCN)[8]. This oscillator is usually entrained to a 24-h rhythm by environmental lighting conditions, which are perceived in the retina by rods, cones and intrinsically photosensitive retinal ganglion cells[9].

Based on the photoperiodic information transduced from the retina via the SCN to the pineal gland, melatonin is secreted during darkness after de-novo synthesis from tryptophan[10]. This nocturnal melatonin signal is proportional to the length of the night, thus encoding not only circadian, but also seasonal variations in the photoperiod[11]. In so-called photoperiodic animals, like the Siberian hamster, these seasonal variations in melatonin output may have a profound influence on the regulation of reproduction[12,13], prolactin secretion[14], as well as coat color[15]. The nocturnal secretion of melatonin is generally independent of an animal’s active period: in both nocturnal and diurnal species, melatonin levels rise during darkness[6].

Melatonin synthesis is not exclusively located in the pineal gland, but has also been described in numerous peripheral organs, such as the retina[16], bone marrow[17], skin[18], Harderian gland[19], platelets[20], lymphocytes[21], testes[22], and in the gastrointestinal tract[23]. Data on messenger RNA expression of two key enzymes responsible for melatonin synthesis, arylalkyamine-N-acetyltransferase and hydoxyindole-O-methyltransferase, suggest that even more peripheral organs may be able to produce this hormone[24].

So far, the physiological significance of extrapineal sites of melatonin synthesis remains unclear. However, besides its relevance in the time-keeping system, melatonin has been demonstrated to be a powerful radical scavenger[25]; it is tempting to assume that extrapineal melatonin may serve as a tissue protective agent.

MELATONIN AS AN ANTIOXIDANT

Processes of acute inflammation, e.g. sepsis, hemorrhagic shock or ischemia/reperfusion, typically result in an imbalance of oxidative homeostasis with excess generation of reactive oxygen species (ROS) and a relative deficiency of endogenous antioxidants; this state is called oxidative stress. ROS include oxidants, such as peroxynitrite, and free radicals, such as hydroxyl radicals and superoxide; these substances are toxic and may induce lipid peroxidation (LPO), as well as protein, sugar and DNA degradation[26].

The powerful antioxidant capacity of melatonin is usually attributed to its potential to eliminate free radicals by the donation of electrons[27,28]. For example, melatonin may neutralize hydroxyl radicals by forming 3-hydroxymelatonin, which is excreted in the urine[29]. Furthermore, melatonin was demonstrated to interact with toxic reactants like peroxyl radicals[30], singlet oxygen species[31], and hydrogen peroxide[32]. Metabolites of melatonin, including the major hepatic metabolite 6-hydroxymelatonin, as well as N-acetyl-N-formyl-5-methoxykynuramine and N-acetyl-5-methoxykynuramine have been shown to detoxify radicals themselves[32-34]. This powerful pyramid scheme of radical scavenging has been named “the antioxidant cascade of melatonin”[1,34].

In addition to these direct interactions with ROS, melatonin may induce upregulation of the activity of antioxidants and antioxidant enzymes, such as superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GPx) and glutathione reductase (GSR), in the environment of oxidative stress[35,36]. In addition, the pineal hormone may induce downregulation of pro-oxidant enzymes like nitric oxide synthase (NOS)[37,38] and lipoxygenases[39], thus reducing the formation of nitric oxide (NO), superoxide anions, and subsequently peroxynitrite anions.

Both the direct detoxification of radicals, as well as the modification of pro- and antioxidative enzyme activities are thought to be relevant for the pineal hormone to act as a protective substance, for example when administered in models of oxidative stress. This valuable effect appears to be independent of the type of injury and the species investigated. Exogenous melatonin may exhibit beneficial actions in a myriad of models of organ damage; this is especially true for the liver.

HEPATOPROTECTION BY MELATONIN ADMINISTRATION

With respect to its hepatoprotective effects, countless publications have demonstrated that exogenous melatonin may be used successfully to treat a great variety of different pathophysiological conditions[40-146]: Table Table11 gives an overview of the hepatoprotective effects of exogenous melatonin administration, without the pretension of being complete. Included in this summary are investigations mainly presenting a model of liver damage in vivo, evaluating parameters of hepatic integrity as a major endpoint, and the administration of melatonin as the primary therapeutic agent. Studies on chronic disease development, aging, investigations on nutritional or dietary changes, exercise-induced stress, remote organ injuries with the liver as a secondary target, as well as investigations on tumor development, cancer progression and liver metastases were excluded.

Table 1
Hepatoprotective effects of melatonin in different models of stress

Based on this extraordinary pool of data, treatment with melatonin appears to be a versatile hepatoprotective strategy in models of experimental liver injury as demonstrated in vivo for rats, mice and chicks. There are remarkable variations concerning both the route of melatonin administration, as well as the dose given, the latter ranging a thousand-fold from 100 μg/kg[93,124] to 100 mg/kg[77] melatonin. Only limited data are available on dose-response relationships, and most studies did not include measurements of plasma melatonin levels. Furthermore, it should be mentioned that in some investigations, melatonin was given either as a single dose or repetitively - in some publications for weeks - as a pretreatment, before or while the damage was induced. Unfortunately, not all researchers used melatonin as a therapeutic substance following the infliction of damage, although this would be of high relevance for the evaluation of its clinical use.

Nevertheless, all these studies show similar or even identical results concerning the hepatoprotective effects of treatment with melatonin. Improvements are consistently demonstrated for - but not limited to - parameters of antioxidant enzymes, hepatocellular integrity, interleukin response, NO signaling, and survival.

Antioxidant effects

A strong antioxidant effect of melatonin seems evident as almost all investigators describe that in liver homogenates, melatonin strongly attenuated hepatic LPO[40-49,53-99,102,103,106-114,116-123,125-146], usually measured by means of malondialdehyde quantification. Furthermore, melatonin appears to increase the activity and/or expression of hepatic antioxidant enzymes, such as GSH, GPx and SOD, after most types of injury[40-49,53-63,66-93,97-99,103,106-123,125-127,130-146]. Many investigators also report an increase in hepatic catalase after melatonin treatment[44,71,78,83-85,89,108,111,115,116,118,125,132,135,139].

Hepatocellular integrity

Administration of the pineal hormone appears to reduce the rise in serum enzyme levels of aspartate transaminase, alanine transaminase, lactate dehydrogenase, alkaline phosphatase, γ glutamyl transferase and bilirubin after almost all types of injury, indicating that the extent of cell damage was reduced[40-62,66-68,77,83-92,94-96,98-103,111-114,116-120,125-127,130-146]. This is supported by histopathology results when performed, showing that animals treated with melatonin typically presented with reduced hepatocellular necrosis or attenuated infiltration of polymorphonuclear granulocytes. Reduced hepatic levels of myeloperoxidase further indicate that neutrophil granulocyte infiltration was strongly reduced by the pineal hormone[41,55,67,108,109,111,134,143].

Interleukin response

With respect to interleukin signaling, melatonin was reported to suppress the formation of pro-inflammatory cytokines such as tumor necrosis factor α, interleukin (IL)-1, IL-1β, IL-6, as well as the cellular interleukin response protein, nuclear factor κ-light-chain-enhancer of activated B cells[42,43,53,62,88,99]. This was demonstrated in sepsis and after ischemia/reperfusion, as well as after carbon tetrachloride and dimethylnitrosamine toxicity. Thus, parts of the hepatoprotective actions of the pineal hormone could be based on its suppressive effects on the pro-inflammatory pathway of the immune response.

NO signaling

A large number of studies have investigated the relevance of the NO pathway in the protective effects of melatonin treatment[40,42,43,45,47,49,53,56,57,60,72,73,75,108,125,128,129,142,146]. Melatonin seems to reduce NO release in the vasculature and attenuate the expression of inducible NOS in the liver, as was demonstrated in models of sepsis, ischemia/reperfusion, cholestasis, ionizing radiation, and toxic liver injury with aflatoxins, carbon tetrachloride, methanol, and thioacetamide. As NO reacts with superoxide to form the potentially toxic oxidant peroxynitrite, the reduction in the expression of iNOS may well be another key element in the antioxidant potential of melatonin.

Survival

When investigated, the observed hepatoprotective effects of melatonin were associated with an improvement in survival rate or mean survival time, which was observed in models of sepsis, ischemia/reperfusion, acetaminophen and diquat toxicity, and malaria[41-43,49,53,60,68,101,146].

Taken together, the results from more than 100 experimental studies included here, show convincingly that various regimens of melatonin treatment may be used to reduce hepatic damage in acute liver injury in vivo[40-146]. However, this overview is likely to be incomplete: many other studies indicate similar results for chronic disease development and tumor therapy.

So far, only one investigation has been published regarding hepatoprotection by melatonin in humans: in a prospective study, increased survival, attenuated liver damage and reduced immunological activity after transcatheter arterial chemoembolization (TACE) and melatonin treatment were reported in patients with inoperable advanced hepatocellular carcinoma, compared with control patients who underwent TACE but were not given melatonin[147].

Limitations of melatonin

Despite the enormous amount of data supporting the idea of melatonin as a liver protective agent, it should be noted that there are reports which show no hepatoprotective effect of melatonin in a few models of stress. Daniels et al[148] were unable to demonstrate any benefit of melatonin administration with respect to carbon tetrachloride-induced liver injury in vivo, although ten other studies unanimously showed the value of such a treatment[83-92]. Furthermore, melatonin had no effect on 2-nitropropane-induced LPO in rat liver[149].

Equally interesting and disappointing, melatonin does not appear to be a protective agent with respect to hepatic ethanol toxicity. In a model of acute or chronic ethanol exposure, melatonin administration did not influence hepatic LPO, or GSH and GPx activities in rat[150]. El-Sokkary et al[151] demonstrated that administration of ethanol for 30 d did not increase hepatic LPO in the same species. Yet, a recent study showed that melatonin may reduce ethanol-induced liver injury in terms of reduced hepatocellular injury and inflammatory response in a rodent model[152]. As a consequence, further data are required to resolve the issue on whether melatonin may be helpful in reducing ethanol-associated liver damage.

Both positive and negative findings raise the question of how melatonin’s intense hepatoprotective potential may be mediated. With respect to this matter, it has been suggested that the activation of membrane-bound melatonin receptors may be an important step in the induction of the antioxidant properties of the pineal hormone[35,36].

HEPATIC MELATONIN RECEPTORS

Melatonin receptors in mammals are classified as membrane-bound, high-affinity G-protein coupled receptors, officially named MT1 and MT2 (previous terminology: Mel1a and Mel1b, respectively)[153]. Both receptors are coupled to heterotrimeric G-proteins, and involve signaling through inhibition of cyclic adenosine-monophosphate (cAMP) formation, protein kinase A activity and phosphorylation of cAMP responsive element binding, as well as effects on adenyl cyclases, phospholipase A2 and C, and calcium and potassium channels[154-158]. A third receptor, named MT3, was demonstrated to be equivalent to intracellular quinone-reductase-2[159]. Non-mammalian species express yet another receptor subtype named Mel1c, which is the first type of melatonin receptor to be discovered[160].

In the liver, the presence of MT1, MT2 and MT3 has been reported in various species[161-171]; Table Table22 gives an overview on the current literature demonstrating hepatic melatonin receptor expression or specific iodine ligand binding. So far, there are no original research publications showing proof of hepatic MT1 or MT2 receptors in humans. Some evidence points to the possibility that melatonin receptor expression may exhibit circadian variations; this has also been demonstrated for hepatic MT1 and MT2[163,166-168].

Table 2
Melatonin receptors in the liver of various species

The physiological significance of hepatic melatonin receptors is mostly unknown. Two studies indicated that hepatic melatonin receptors may be involved in regulating blood glucose[164,172]. Melatonin receptor double knock-out mice do exist, and they appear to have a generally unaltered phenotype. So far, there are no reports showing disadvantages regarding the lack of hepatic melatonin receptors under physiological conditions.

Unfortunately, there are currently no reliable antibodies available for MT1 and MT2 receptors[154]. Only a few publications have demonstrated data on the MT1 or MT2 protein[162,173]; the results are either non-specific or cannot easily be reproduced. Thus, additional techniques will be required to convincingly demonstrate melatonin receptor protein in the liver.

Nonetheless, our own laboratory was able to generate preliminary results concerning the immunohistochemical distribution of MT1 in the liver[173]. It appeared that MT1 was primarily localized in the pericentral area of liver lobules. Due to their metabolic state, pericentral fields of the liver are particularly sensitive to ischemic stress, compared to slightly better oxygenated periportal areas. Thus, this differential distribution of melatonin receptors could provide a way of focusing melatonin receptor-dependent liver protection to areas in need. It is tempting to speculate that this pattern of MT1 expression might allow the preferential protection of centrolobular hepatocytes.

Further studies, using different techniques or improved antibodies, will be required to support this idea of differentially distributed hepatic melatonin receptors. Thus, the presence and distribution of both melatonin receptor protein subtypes in the liver remain to be determined.

RECEPTOR-MEDIATED ACTIONS OF MELATONIN IN THE LIVER

Only a few studies have analyzed the significance of melatonin receptors in the hepatoprotective effects of melatonin administration in vivo[50,51,174]. In a model of hemorrhage and resuscitation, the melatonin receptor antagonist luzindole was able to attenuate the protective effects of melatonin pretreatment and therapy with respect to liver function as measured by plasma disappearance rate of indocyanine green[50,51]. However, not all of the beneficial effects of melatonin were abolished. The use of this antagonist may not clarify all aspects of the effects of melatonin administration, as luzindole itself has been demonstrated to have a strong direct antioxidant potential[175], and to reduce LPO in vitro[176].

In the same model of hemorrhagic shock, therapy with the selective melatonin receptor agonist ramelteon improved liver function and hepatic perfusion in rats[174]; this melatonin receptor agonist does not possess any relevant radical scavenging properties[174]. These results point to the possibility that although beneficial, the radical scavenging capacity of melatonin may not be necessary for its protective actions.

This hypothesis is supported by the observation that in other organ systems, the protective potential of melatonin may also be antagonized by luzindole: this antagonist has been reported to abolish the protective capacity of melatonin after myocardial ischemia/reperfusion injury[177], after cyclosporine-A cardiotoxicity[178], in a model of neonatal brain injury[179], and with respect to stress-induced gastric lesions[180].

The following preliminary data from our own research laboratory may have even more impact: in a murine model of sepsis, we were able to demonstrate that the improvements in survival seen after melatonin therapy were not present in melatonin receptor double knock-out mice. This finding indicates once more that membrane-bound melatonin receptors may be responsible for the beneficial effects of melatonin administration.

As a consequence, if (1) no radical scavenging properties are necessary to provide organ protection via melatonin receptor activation[174]; (2) the melatonin receptor antagonist luzindole may abolish almost all protective effects of melatonin[177-180]; and (3) the absence of melatonin receptors impedes the protective action of melatonin administration, then it appears reasonable to conclude that melatonin receptors are necessary to mediate at least some of the beneficial effects of the pineal hormone in peripheral organs.

POTENTIAL INFLUENCE ON HEPATIC GENE EXPRESSION

The specific intracellular signal transduction cascade leading to hepatoprotective effects after melatonin receptor activation is presently unknown. However, a number of hypotheses have been published, suggesting that cAMP responsive element- or estrogen responsive element-containing genes may be regulated by melatonin receptor activation[35,181]. Most certainly, melatonin has a profound influence on hepatocellular gene expression; this has been demonstrated in heat shock protein expression by various investigators[69,73,95]. Our research group was able to present preliminary data showing that melatonin influences different pathways of hepatocellular transcription, including modifications of a variety of heat shock proteins, as well as intense regulation of other membrane-bound receptors and signal transduction factors, in a rat model of hemorrhagic shock[182]. These findings allow the assumption that melatonin therapy may induce beneficial changes with respect to gene transcription in hepatocytes, in the environment of oxidative stress. However, it remains to be determined whether these modifications of hepatic gene expression are indeed mediated by melatonin receptor activation.

FROM BENCH TO BEDSIDE

While the current literature leaves little doubt that melatonin administration may induce hepatoprotective actions[40-146], many questions remain on how this effect may be transduced. The putative signaling cascade, leading from melatonin receptor activation to specific hepatoprotective gene expression profiles, remains to be determined. Based on the evidence available, it appears possible that melatonin receptors mediate the intense protective effects of the pineal hormone in the liver.

To bring this experimental knowledge into clinical use, a pilot study was initiated by Schemmer et al[183] in Germany to evaluate the use of melatonin in patients undergoing major liver resections. Should this investigation be successful, this would open the door for yet another important indication for the use of melatonin in human liver surgery: as an adjunct to reduce ischemia/reperfusion injury in liver transplantation. The research group of Freitas and Vairetti has already demonstrated in two studies that melatonin may reduce cold ischemic injury in rat liver[184,185], and suggested that the pineal hormone may be useful in the event of liver transplantation. This idea was supported by Casillas-Ramírez in a review on liver transplantation[186]. Thus, melatonin administration could be beneficial in patients not only to reduce damage to the transplant, but also to serve as a protective agent for the attenuation of reperfusion injury.

Future studies will demonstrate whether melatonin will meet our high expectations not only in the laboratory, but also for our patients. However, the currently available literature allows us to believe that melatonin will successfully continue its way from bench to bedside as a powerful hepatoprotective agent.

Acknowledgments

The author would like to thank Dr. Larsen R, Professor, Dr. Rensing H, Professor, Dr. Volk T, Professor, Fink T and Wolf B for their encouragement and support.

Footnotes

Supported by (in part) Grants from the European Society of Anesthesiology and the HOMFOR Homburger Forschungsförderung

Peer reviewer: Shiu-Ming Kuo, MD, University at Buffalo, 15 Farber Hall, 3435 Main Street, Buffalo, NY 14214, United States

S- Editor Sun H L- Editor Webster JR E- Editor Zheng XM

References

1. Reiter RJ, Tan DX, Manchester LC, Pilar Terron M, Flores LJ, Koppisepi S. Medical implications of melatonin: receptor-mediated and receptor-independent actions. Adv Med Sci. 2007;52:11–28. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PMC free article] [PubMed]
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. [PubMed]
6. Arendt J. Melatonin and the pineal gland: influence on mammalian seasonal and circadian physiology. Rev Reprod. 1998;3:13–22. [PubMed]
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. [PubMed]
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. [PubMed]
9. Reppert SM, Weaver DR. Coordination of circadian timing in mammals. Nature. 2002;418:935–941. [PubMed]
10. Sugden D. Melatonin biosynthesis in the mammalian pineal gland. Experientia. 1989;45:922–932. [PubMed]
11. Goldman BD. Mammalian photoperiodic system: formal properties and neuroendocrine mechanisms of photoperiodic time measurement. J Biol Rhythms. 2001;16:283–301. [PubMed]
12. Reiter RJ. The melatonin rhythm: both a clock and a calendar. Experientia. 1993;49:654–664. [PubMed]
13. Reiter RJ. The pineal and its hormones in the control of reproduction in mammals. Endocr Rev. 1980;1:109–131. [PubMed]
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. [PubMed]
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. [PubMed]
16. Tosini G, Menaker M. The clock in the mouse retina: melatonin synthesis and photoreceptor degeneration. Brain Res. 1998;789:221–228. [PubMed]
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. [PubMed]
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. [PubMed]
19. Djeridane Y, Touitou Y. Melatonin synthesis in the rat harderian gland: age- and time-related effects. Exp Eye Res. 2001;72:487–492. [PubMed]
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. [PubMed]
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. [PubMed]
22. Tijmes M, Pedraza R, Valladares L. Melatonin in the rat testis: evidence for local synthesis. Steroids. 1996;61:65–68. [PubMed]
23. Bubenik GA. Gastrointestinal melatonin: localization, function, and clinical relevance. Dig Dis Sci. 2002;47:2336–2348. [PubMed]
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. [PubMed]
25. Reiter R, Tang L, Garcia JJ, Muñoz-Hoyos A. Pharmacological actions of melatonin in oxygen radical pathophysiology. Life Sci. 1997;60:2255–2271. [PubMed]
26. Cuzzocrea S, Reiter RJ. Pharmacological actions of melatonin in acute and chronic inflammation. Curr Top Med Chem. 2002;2:153–165. [PubMed]
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. [PubMed]
28. Hardeland R. Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance. Endocrine. 2005;27:119–130. [PubMed]
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. [PubMed]
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. [PubMed]
31. Cagnoli CM, Atabay C, Kharlamova E, Manev H. Melatonin protects neurons from singlet oxygen-induced apoptosis. J Pineal Res. 1995;18:222–226. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
41. Sener G, Toklu H, Kapucu C, Ercan F, Erkanli G, Kaçmaz A, Tilki M, Yeğen BC. Melatonin protects against oxidative organ injury in a rat model of sepsis. Surg Today. 2005;35:52–59. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
55. Sener G, Tosun O, Sehirli AO, Kaçmaz A, Arbak S, Ersoy Y, Ayanoğlu-Dülger G. Melatonin and N-acetylcysteine have beneficial effects during hepatic ischemia and reperfusion. Life Sci. 2003;72:2707–2718. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PMC free article] [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
67. Sener G, Sehirli AO, Ayanoğlu-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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
75. Ozen H, Karaman M, Ciğremiş Y, Tuzcu M, Ozcan K, Erdağ D. Effectiveness of melatonin on aflatoxicosis in chicks. Res. Vet Sci. 2009;86:485–489. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
86. Kus I, Ogeturk M, Oner H, Sahin S, Yekeler H, Sarsilmaz M. Protective effects of melatonin against carbon tetrachloride-induced hepatotoxicity in rats: a light microscopic and biochemical study. Cell Biochem Funct. 2005;23:169–174. [PubMed]
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. [PubMed]
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. [PubMed]
89. Noyan T, Kömüroğlu U, Bayram I, Sekeroğlu MR. Comparison of the effects of melatonin and pentoxifylline on carbon tetrachloride-induced liver toxicity in mice. Cell Biol Toxicol. 2006;22:381–391. [PubMed]
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. [PubMed]
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. [PMC free article] [PubMed]
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. [PubMed]
93. Manda K, Bhatia AL. Prophylactic action of melatonin against cyclophosphamide-induced oxidative stress in mice. Cell Biol Toxicol. 2003;19:367–372. [PubMed]
94. Kwak CS, Mun KC. The beneficial effect of melatonin for cyclosporine hepatotoxicity in rats. Transplant Proc. 2000;32:2009–2010. [PubMed]
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. [PubMed]
96. Kurus M, Esrefoglu M, Sogutlu G, Atasever A. Melatonin prevents cyclosporine-induced hepatotoxicity in rats. Med Princ Pract. 2009;18:407–410. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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 diquat-induced lipid peroxidation in vivo as assessed by the measurement of F2-isoprostanes. J Pineal Res. 2006;40:326–331. [PubMed]
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. [PubMed]
102. Oz E, Ilhan MN. Effects of melatonin in reducing the toxic effects of doxorubicin. Mol Cell Biochem. 2006;286:11–15. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
106. El-Missiry MA. Prophylactic effect of melatonin on lead-induced inhibition of heme biosynthesis and deterioration of antioxidant systems in male rats. J Biochem Mol Toxicol. 2000;14:57–62. [PubMed]
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. [PubMed]
108. Kurcer Z, Oğuz 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. [PubMed]
109. Jahovic N, Cevik H, Sehirli AO, Yeğen BC, Sener G. Melatonin prevents methotrexate-induced hepatorenal oxidative injury in rats. J Pineal Res. 2003;34:282–287. [PubMed]
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. [PubMed]
111. Ohta Y, Kongo M, Sasaki E, Ishiguro I, Harada N. Protective effect of melatonin against alpha-naphthylisothiocyanate-induced liver injury in rats. J Pineal Res. 2000;29:15–23. [PubMed]
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. [PubMed]
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-naphthylisothiocyanate-induced liver injury in rats. J Cell Biochem. 2001;80:461–470. [PubMed]
114. Ohta Y, Kongo M, Kishikawa T. Preventive effect of melatonin on the progression of alpha-naphthylisothiocyanate-induced acute liver injury in rats. J Pineal Res. 2003;34:185–193. [PubMed]
115. Lankoff A, Banasik A, Nowak M. Protective effect of melatonin against nodularin-induced oxidative stress. Arch Toxicol. 2002;76:158–165. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
121. Melchiorri D, Reiter RJ, Attia AM, Hara M, Burgos A, Nistico G. Potent protective effect of melatonin on in vivo paraquat-induced oxidative damage in rats. Life Sci. 1995;56:83–89. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
133. Bülbüller N, Akkuş MA, Cetinkaya Z, Ilhan YS, Ozercan I, Kirkil C, Doğru O. Effects of melatonin and lactulose on the liver and kidneys in rats with obstructive jaundice. Pediatr Surg Int. 2002;18:677–680. [PubMed]
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. [PubMed]
135. Padillo FJ, Cruz A, Navarrete C, Bujalance I, Briceño J, Gallardo JI, Marchal T, Caballero R, Túnez I, Muntané J, et al. Melatonin prevents oxidative stress and hepatocyte cell death induced by experimental cholestasis. Free Radic Res. 2004;38:697–704. [PubMed]
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. [PubMed]
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. [PubMed]
138. Muñoz-Castañeda JR, Túnez I, Herencia C, Ranchal I, González R, Ramírez LM, Arjona A, Barcos M, Espejo I, Cruz A, et al. 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. [PubMed]
139. Emre MH, Polat A, Eşrefoğlu 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. [PubMed]
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. [PubMed]
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. [PubMed]
142. Taysi S, Koc M, Büyükokuroğlu 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. [PubMed]
143. Sener G, Jahovic N, Tosun O, Atasoy BM, Yeğen BC. Melatonin ameliorates ionizing radiation-induced oxidative organ damage in rats. Life Sci. 2003;74:563–572. [PubMed]
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. [PubMed]
145. El-Missiry MA, Fayed TA, El-Sawy MR, El-Sayed AA. Ameliorative effect of melatonin against gamma-irradiation-induced oxidative stress and tissue injury. Ecotoxicol Environ Saf. 2007;66:278–286. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
150. Genç S, Gürdöl F, Oner-Iyidoğan Y, Onaran I. The effect of melatonin administration on ethanol-induced lipid peroxidation in rats. Pharmacol Res. 1998;37:37–40. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PMC free article] [PubMed]
155. von Gall C, Stehle JH, Weaver DR. Mammalian melatonin receptors: molecular biology and signal transduction. Cell Tissue Res. 2002;309:151–162. [PubMed]
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. [PubMed]
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. [PubMed]
158. Barrett P, Morris M, Choi WS, Ross A, Morgan PJ. Melatonin receptors and signal transduction mechanisms. Biol Signals Recept. 1999;8:6–14. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
177. Lochner A, Genade S, Davids A, Ytrehus K, Moolman JA. Short- and long-term effects of melatonin on myocardial post-ischemic recovery. J Pineal Res. 2006;40:56–63. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PMC free article] [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]

Articles from World Journal of Gastroenterology : WJG are provided here courtesy of Baishideng Publishing Group Inc