Ionizing radiation is classified as a potent carcinogen, and its injury to living cells is, to a large extent, due to oxidative stress. The molecule most often reported to be damaged by ionizing radiation is DNA. Hydroxyl radicals (.OH), considered the most damaging of all free radicals generated in organisms, are often responsible for DNA damage caused by ionizing radiation. Melatonin, N-acetyl-5-methoxytryptamine, is a well-known antioxidant that protects DNA, lipids, and proteins from free-radical damage. The indoleamine manifests its antioxidative properties by stimulating the activities of antioxidant enzymes and scavenging free radicals directly or indirectly. Among known antioxidants, melatonin is a highly effective scavenger of .OH. Melatonin is distributed ubiquitously in organisms and, as far as is known, in all cellular compartments, and it quickly passes through all biological membranes. The protective effects of melatonin against oxidative stress caused by ionizing radiation have been documented in In vitro and In vivo studies in different species and in In vitro experiments that used human tissues, as well as when melatonin was given to humans and then tissues collected and subjected to ionizing radiation. The radioprotective effects of melatonin against cellular damage caused by oxidative stress and its low toxicity make this molecule a potential supplement in the treatment or co-treatment in situations where the effects of ionizing radiation are to be minimized.
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References
1.
TouleR.Radiation-induced DNA damage and its repair. Int J Radiat Biol51: 573–589, 1987.
2.
AmesBN, GoldLS. Endogenous mutagens and the causes of aging and cancer. Mutat Res250: 3–16, 1991.
3.
HalliwellB, AruomaOI. DNA damage by oxygen-derived speciesFEBS Lett281:9–19, 1991.
BeckerD, SevillaMD. The chemical consequences of radiation damage to DNA. Adv Radiat Biol17: 121–179, 1993.
6.
IkushimaT, AritomiH, MorisitaJ.Radioadaptive response: Efficient repair of radiation-induced DNA damage in adapted cells. Mutat Res358: 193–198, 1996.
7.
WallaceSS. Enzymatic processing of radiation-induced free radical damage in DNA. Radiat Res150: S60–S79, 1998.
8.
WardJF. DNA damage produced by ionizing radiation in mammalian cells: Identities, mechanisms of formation, and reparability. Prog Nucl Acid Res Mol Biol35: 95–125, 1988.
9.
Martinez-CayuelaM.Oxygen free radicals and human disease. Biochimie77: 147–161, 1955.
10.
SiesH.Biochemistry of oxidant stress. Angew Chem Int Ed Engl25: 1058–1071, 1986.
11.
De ZwartLL, MeermanJHN, CommandeurJNM, VermeulenNPE. Biomarkers of free radical damage applications in experimental animals and in humans. Free Radic Biol Med26: 202–226, 1999.
12.
Vijayalaxmi LealBZ, DeahlTS, MeltzML. Variability in adaptive response to low dose radiation in human blood lymphocytes: Consistent results from chromosome aberrations and micronuclei. Mutat Res348: 45–50, 1995.
13.
SteenkenS.Purine bases, nucleosides, and nucleotides: Aqueous solution redox chemistry and transformation reactions of their radical cations and e.- and OH adducts. Chem Rev89: 503–520, 1989.
14.
BreenAP, MurphyJA. Reactions of oxyl radicals with DNA. Free Radic Biol Med18: 1033–1077, 1995.
15.
HalliwellB.Reactive oxygen species and the central nervous system. J Neurochem59: 1609–1623, 1992.
16.
OshinoN, ChanceB, SiesH, BücherT.The role of H2O2 generation in perfused rat liver and the reaction of catalase compound I and hydrogen donors. Arch Biochem Biophys154: 117–131, 1993.
17.
CadetJ, DelatourT, DoukiT, GasparuttoD, PougetJP, RavanatJL, SauvaigoS.Hydroxyl radicals and DNA base damage. Mutat Res424: 9–21, 1999.
18.
KasaiH, CrainF, KuchinoY, NishimuraN, OotsuyamaA, TanookaH.Formation of 8-hydroxyguanine moiety in cellular DNA by agents producing oxygen radicals and evidence for its repair. Carcinogenesis7: 1849–1851, 1986.
19.
GajewskiE, RaoG, NackerdienZ, DizdarogluM.Modification of DNA bases in mammalian chromatin by radiation-generated free radicals. Biochemistry29: 7876–7882, 1990.
20.
WoodML, DizdarogluM, GajewskiE, EssigmannJM. Mechanistic studies of ionizing radiation and oxidative mutagenesis: Genetic effects of a single 8-hydroxyguanine (7-hydro-8-oxoguanine) residue inserted at a unique site in a viral genome. Biochemistry29: 7024–7032, 1990.
21.
ChengKC, CahillDS, KasaiH, NishimuraS, LoebLA. 8-Hydroxyguanine, an abundant form of oxidative DNA damage, causes G→T and and A→X substitutions. J Biol Chem267: 166–172, 1992.
22.
TchouJ, GrollmanAP. Repair of DNA containing the oxidatively damaged base, 8-oxoguanine. Mutat Res299: 277–287, 1993.
23.
FloydRA. The role of 8-hydroxydeoxyguanosine in carcinogenesis. Carcinogenesis11: 1447–1450, 1990.
24.
Fischer-NielsenA, JedingIB, LoftS.Radiation-induced formation of 8-hydroxy-2′-deoxyguanosine and its prevention by scavengers. Carcinogenesis15: 1609–1612, 1994.
25.
HaegeleAD, WolfeP, ThompsonHJ. X-radiation induces 8-hydroxy-2′-deoxyguanosine formation in vivo in rat mammary gland DNA. Carcinogenesis19: 1319–1321, 1998.
26.
EliaMC, DcLucaJG, BradleyMO. Significance and measurement of DNA double strand breaks in mammalian cells. Pharmacol Ther51: 291–327, 1991.
27.
SankaranarayananK.Ionizing radiation and genetic risks X. The potential “disease phenotypes” of radiation-induced genetic damage in humans: Perspectives from human molecular biology and radiation genetics. Mutat Res429: 45–83, 1999.
28.
OlivieriG, BodycoteJ, WolffS.Adaptive response of human lymphocytes to low concentrations of radioactive thymidine. Science223: 594–597, 1984.
29.
Vijayalaxmi ReiterRJ, MeltzML. Melatonin protects human blood lymphocytes from radiation-induced chromosome damage. Mutat Res346: 23–31, 1995.
30.
Vijayalaxmi ReiterRJ, SewerynekE, PoeggelerB, LealBZ, MeltzML. Marked reduction of radiation-induced micronuclei in human blood lymphocytes pre-treated with melatonin. Radiat Res143: 102–106, 1995.
31.
Vijayalaxmi ReiterRJ, HermanTS, MeltzML. Melatonin and radio-protection from genetic damage: In vivo/in vitro studies with human volunteers. Mutat Res371: 221–228, 1996.
32.
Vijayalaxmi ReiterRJ, HermanTS, MeltzML. Melatonin reduces gamma radiation-induced primary DNA damage in human blood lymphocytes. Mutat Res397: 203–208, 1998.
33.
Vijayalaxmi ReiterRJ, MeltzML, HermanTS. Melatonin: Possible mechanisms involved in its ‘radioprotective’ effect. Mutat Res404: 187–189, 1998.
34.
EdwardsJC, ChapmanD, CrampWA, YatvinMB. The effects of ionizing radiation on biomembrane structure and function. Prog Biophys Mol Biol43: 71–93, 1984.
35.
VermaSP, SonwalkerN.Structural changes in plasma membranes prepared from irradiated Chinese hamster V79 cells as revealed by Raman spectroscopy. Radiat Res126: 27–35, 1991.
36.
LizardG, FournelS, GenestierL, DhedinN, ChaputC, HacherM, MutinM, PanayeG, RevillardJP. Kinetics of plasma membrane and mitochondrial alterations in cells undergoing apoptosis. Cytometry21: 275–283, 1995.
37.
SamuniAM, BarenholzY, CrommelinDJA, ZuidamNJ. γ-Irradiation damage to liposomes differing in composition and their protection by nitroxides. Free Radic Biol Med23: 972–979, 1997.
38.
ParasassiT, GiustiAM, GrattonE, MonacoE, RaimondiM, RavagnanG, SaporaO.Evidence for an increase in water concentration in bilayers after oxidative damage of phospholipids induced by ionizing radiation. Int J Radiat Biol65: 329–334, 1994.
39.
ParasassiT, RavagnanG, SaporaO, GrattonE.Membrane oxidative damage induced by ionizing radiation detected by diphenylhexatriene fluorescence lifetime distributions. Int J Radiat Biol61: 791–796, 1992.
40.
GiustiAM, RaimondiM, RavagnanG, SaporaO, ParasassiT.Human cell membrane oxidative damage induced by single and fractionated doses of ionizing radiation: A fluorescence spectroscopy study. Int J Radiat Biol74: 595–605, 1998.
41.
ChatterjeeSN, AgarwalS.Liposomes as membrane model for study of lipid peroxidation. Free Radic Biol Med4: 51–72, 1988.
42.
ParasassiT, SaporaO, GiustiAM, De StasioG, RavagnanG.Alteration in erythrocyte membrane lipids induced by low doses of ionizing radiation as revealed by 1,6-diphenyl-1, 3,5-hexatriene fluorescence lifetime. Int J Radiat Biol59: 59–69, 1991.
43.
UedaT, ToyoshimaY, KushihahiT, HishidaT, YasuharaH.Effect of dimethyl sulfoxide pretreatment on activities of lipid peroxide formation, superoxide dismutase. and glutathione peroxidase in the mouse liver after whole-body irradiation. J Toxicol Sci18: 239–244, 1993.
44.
UedaT, ToyoshimaY, MoritaniT, RiK, OtsukiN, KushihashiT, YasuharaH, HishidaT.Protective effect of dipyridamole against lethality and lipid peroxidation in liver and spleen of the ddY mouse after whole-body irradiation. Int J Radiat Biol69: 199–204, 1996.
45.
SlyshenkovVS, OmelyanchikSN, MoiseenokAG, TrebukhinaRV, WojtczakL.Pantothenol protects rats against some deleterious effects of gamma radiation. Free Radic Biol Med24: 894–899, 1998.
46.
OnoSI, CaiL, CherianMG. Effects of gamma radiation on levels of brain metallothionein and lipid peroxidation in transgenic mice. Radial Res150: 52–57, 1998.
47.
CurtisMT, GilforD, FarberJL. Lipid peroxidation increases the molecular order of microsomal membranes. Arch Biochem Biophys235: 644–649, 1984.
48.
MaiorinoM, CoassinM, RoveriA, UrsiniF.Microsomal lipid peroxidation: Effect of vitamin E and its functional interaction with phospholipid hydroperoxide glutathione peroxidase. Lipids24: 721–726, 1989.
49.
ArtebryVE, PryorWA, JiangL, SehnenSS, FosterWM, AbramsRA, WilliamsJR, WharamMD, RisbyTH. Breath ethane generation during clinical total body irradiation as a marker of oxygen-free-radical-mediated lipid peroxidation: A case study. Free Radic Biol Med17: 569–576, 1994.
GarciaJJ, ReiterRJ, OrtizGG, OhCS, TangL, YuBP, EscamesG.Melatonin enhances tamoxifen's ability to prevent the reduction in microsomal membrane fluidity induced by lipid peroxidation. J Membr Biol162: 59–65, 1998.
52.
BerroudA, Le RoyA, VoisinP.Membrane oxidative damage induced by ionizing radiation detected by fluorescence polarization. Radiat Environ Biophys35: 289–295, 1996.
53.
MarshD.Spin-label answers to lipid-protein interactions. Trends Biochem Sci8: 330–333, 1983.
54.
AfanasyevVN, KorolBA, MatylevichNP, PechatnikovVA, UmanskySR. The use of flow cytometry for the investigation of cell death. Cytometry14: 603–609, 1993.
55.
ZimmerG.Fluidity of cell membranes in the presence of some drugs and inhibitors. In: KatesM, MansonLA Eds. Biomembranes. New York: Plenum, pp 169–203, 1984.
56.
PohlLR. An immunochemical approach of identifying and characterizing protein targets of toxic reactive metabolites. Chem Res Toxicol6: 786–793, 1993.
57.
Le MaireM, ThauvetteL, De ForestaB, VielA, BeauregardG, PoitierM.Effects of ionizing radiation on proteins: Evidence of nonrandom fragmentation and caution in the use of the method for determination of molecular mass. Biochem J267: 431–439, 1990.
58.
JhunE, JhunBH, JonesLR, JungCY. Direct effects of ionizing radiation on integral membrane proteins. J Biol Chem266: 9403–9407, 1991.
59.
WolffS.Aspects of the adaptive response to very low doses of radiation and other agents. Mutat Res358: 135–142, 1996.
60.
WolffS.The adaptive response in radiobiology: Evolving insights and implications. Environ Health Perspect106: 277–283, 1998.
61.
FeinendegenLE. The role of adaptive responses following exposure to ionizing radiation. Hum Exp Toxicol18: 426–432, 1999.
62.
ZhangH, ZhengRL, WeiZQ, LiWJ, GaoQX, ChenWQ, WangZH, HeJ, LiangJP, HanGW, HuangT, LiQ, XieHM, ZhangSM, CaiXC. Effects of pre-exposure of mouse testis with low-dose 16O8+ ions or 60Co γ-rays on sperm shape abnormalities, lipid peroxidation, and superoxide dismutase (SOD) activity induced by subsequent high-dose irradiation. Int J Radiat Biol73: 163–167, 1998.
63.
KojimaS, MatsukiO, NomuraT, KuboderaA, HondaY, HondaS, TanookaH, WakasugiH, YamaokaK.Induction of mRNAs for glutathione synthesis-related proteins in mouse liver by low doses of γ-rays. Biochim Biophys Acta1381: 312–318, 1998.
64.
KojimaS, MatsukiO, NomuraT, YamaokaK, TakahashiM, NikiE.Elevation of antioxidant potency in the brain of mice by low-dose γ-ray irradiation and its effect on l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced brain damage. Free Radic Biol Med26: 388–395, 1999.
65.
RileyPA. Free radicals in biology: Oxidative stress and the effects of ionizing radiation. Int J Radiat Biol65: 27–33, 1994.
ReiterRJ. The pineal gland and melatonin in relation to aging: A summary of the theories and of the data. Exp Gerontol30: 199–212, 1995.
77.
CostaEJX, LopesRH, Lamy-FreundMT. Solubility of pure bilayers to melatonin. J Pineal Res19: 123–126, 1995.
78.
ShidaCS, CastnicciAML, Lamy-FreundMT. High melatonin solubility in aqueous media. J Pineal Res16: 198–201, 1994.
79.
CostaEJX, ShidaCS, BiaggiMH, ItoAS, Lamy-FreundMT. How melatonin interacts with lipid bilayers: A study by fluorescence and ESR spectroscopies. FEBS Lett416: 103–106, 1997.
80.
CerauloL, FerrugiaM, TesoriereL, SegretoS, LivreaMA, LiveriTV. Interactions of melatonin with membrane models: Portioning of melatonin in AOT and lecithin reversed micelles. J Pineal Res26: 108–112, 1999.
81.
Menendez-PelaezA, ReiterRJ. Distribution of melatonin in mammalian tissues: The relative importance of cytosolic versus nuclear localization. J Pineal Res15: 59–69, 1993.
82.
Menendez-PelaezA, PoeggelerB, ReiterRJ, Barlow-WaldenLR, PablosMI, TanDX. Nuclear localization of melatonin in different mammalian tissues: Immunocytochemical and radioimmunoassay evidence. J Cell Biochem53: 372–382, 1993.
83.
FinnocchiaroLME, GlikinGG. Modulation of subcellular distribution of calmodulin by melatonin in MDCK cells. J Pineal Res24: 22–34, 1998.
84.
ReiterRJ, GuerreroJM, GarciaJJ, Acuna-CastroviejoD.Reactive oxygen intermediates, molecular damage and aging: Relation to melatonin. Ann N Y Acad Sci854: 410–424, 1998.
85.
MorganJP. Molecular signaling via the melatonin receptor. Adv Pineal Res5: 191–198, 1991.
86.
PoonAMS, PangSF. Modulation of 2[123I]iodomelatonin binding sites in the guinea pig spleen by melatonin injection is dependent on the dose and period but not the time. Life Sci54: 1411–1418, 1994.
87.
ReppertSM, WeaverDR, EbisawaT.Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. Neuron13: 1177–1185, 1994.
88.
Acuna-CastroviejoD, PablosMI, Menendez-PelaezA, ReiterRJ. Melatonin receptors in purified cell nuclei of liver. Res Commun Chem Pathol Pharmacol82: 253–256, 1993.
89.
Acuna-CastroviejoD, ReiterRJ, Menendez-PelaezA, PablosMI, BurgosA.Characterization of high-affinity binding sites in purified cell nuclei of rat liver. J Pineal Res16: 100–113, 1994.
90.
Becker-AndreM, WiesenbergI, Schaeren-WiemersN, AndreE, MissbachM, SouretJH, CarlbergC.Pineal hormone melatonin binds and activates an orphan of the nuclear receptor superfamily. J Biol Chem269: 28531–28534, 1994.
91.
CarlbergC, WiesenbergI.The orphan receptor family RZR/ROR, melatonin and 5-lipoxygenase: An unexpected relationship. J Pineal Res18: 171–178, 1995.
92.
HardelandR, ReiterRJ, PoeggelerB, TanDX. The significance of the metabolism of the neurohormone melatonin: Protection and formation of bioactive substances. Neurosci Biobehav Rev17: 347–357, 1993.
93.
PoeggelerB, ReiterRJ, HardelandR, SewerynekE, MelchiorriD, Barlow-WaldenLR. Melatonin, a mediator of electron transfer and repair reactions, acts synergistically with the chain-breaking antioxidants ascorbate, trolox, and glutathione. Neuroendocrinol Lett17: 87–92, 1995.
94.
Huerto-DelgadilloL, Anton-TayF, Benitz-KingG.Effects of melatonin on microtubule assembly depend on hormone concentration: Role of melatonin as a calmodulin antagonist. J Pineal Res13: 55–62, 1992.
VaughanGM, TaylorTJ, PruittBAJ, MasonADJ. Pineal function in bums: Melatonin is not a marker for general sympathetic activity. J Pineal Res2: 1–12, 1985.
97.
KhooryR, StemmeD.Plasma melatonin levels in patients suffering from colorectal carcinoma. J Pineal Res5: 251–258, 1988.
98.
WestSK, OosthuizenJM. Melatonin levels are decreased in rheumatoid arthritis. J Basic Clin Physiol Pharmacol3: 33–40, 1992.
99.
KennedySH, KutcherSP, RalewskiE, BrownGM. Nocturnal melatonin and 24-hour 6-sulphatoxymelatonin levels in various phases of bipolar effective disorder. Psychiatry Res63: 219–222, 1996.
100.
PangSF, AllenAE. Extra-pineal melatonin in the retina: Its regulation and physiological function. In: ReiterRJ Ed. Pineal Research Review. New York: Alan R. Liss, Vol. 4: pp55–95, 1986.
101.
HuetherG, PoeggelerB, ReimerA, GeorgeA.Effect of tryptophan administration on circulating melatonin levels in chicks and rats: Evidence for stimulation of melatonin synthesis and release in the gastrointestinal tract. Life Sci51: 945–953, 1992.
102.
ItohMT, IshizukaB, KudoY, FusamaS, AmemiyaA, SumiY.Detection of melatonin and serotonin N-acetyltransferase and hydroxyindole-O-methyltransferase in rat ovary. Mol Cell Endocrinol136: 7–13, 1997.
103.
TijimesM, PedrazaR, ValladaresL.Melatonin in the rat testis: Evidence for local synthesis. Steroids61: 65–68, 1996.
104.
TanDX, ManchesterLC, ReiterRJ, QiW, ZhangM, WeintraubST, CabreraJ, SainzRM, MayoJC. Identification of highly elevated levels of melatonin in bone marrow: Its origin and significance. Biochim Biophys Acta1472: 206–214, 1999.
PoeggelerB, ReiterRJ, HardelandR, TanDX, Barlow-WaldenLR. Melatonin and structurally related endogenous indoles act as potent electron donors and radical scavengers in vitro.Redox Rep2: 179–184, 1996.
107.
MatuszakZ, ReszkaKJ, ChignellCF. Reaction of melatonin and related indoles with hydroxyl radicals: EPR and spin trapping investigations. Free Radic Biol Med23: 367–372, 1997.
108.
SusaN, UenoS, FurukawaY, UedaJ, SugiyamaM.Potent protective effect of melatonin on chromium (VI) -induced DNA single-strand breaks, cytotoxicity, and lipid peroxidation in primary cultures of rat hepatocytes. Toxicol Appl Pharmacol144: 377–384, 1997.
109.
LiXJ, ZhangLM, GuJ, ZhangAZ, SunFY. Melatonin decreases production of hydroxyl radical during cerebral ischemia-reperfusion. Chung Kuo Yao Li Hsueh Pao18: 394–396, 1997.
110.
TanDX, ManchesterLC, ReiterRJ, PlummerBF, HardiesLJ, WeintraubST, Vijayalaxmi ShepherdAMM. A novel melatonin metabolite, cyclic 3-hydroxymelatonin: A biomarker of in vivo hydroxyl radical generation. Biochem Biophys Res Commun253: 614–6201998.
111.
StasicaP, UlanskiP, RosiakJM. Melatonin as a hydroxyl radical scavenger. J Pineal Res25: 65–66, 1998.
112.
PähklaR, ZilmerM, KullisaarT, RägoL.Comparison of the antioxidant activity of melatonin and pinoline in vitro.J Pineal Res24: 96–101, 1998.
113.
OkadaS, NakamuraN, SasakiK.Radioprotection of intracellular genetic material. In: NygaardOF, SimicMG Eds. Radioprotectors and Anticarcinogens. New York: Academic Press, pp 339–356, 1983.
114.
PieriC, MarraM, MoroniF, RecchioniR, MarcheselliF.Melatonin: A peroxyl radical scavenger more effective than vitamin E. Life Sci55: PL271–PL276, 1994.
115.
PieriC, MoroniF, MarraM, MarcheselliF, RecchioniR.Melatonin is an efficient antioxidant. Arch Gerontol Geriatr20: 159–165, 1995.
116.
ScaianoJC. Exploratory laser flash photolysis study of free radical reactions and magnetic field effects in melatonin chemistry. J Pineal Res19: 189–195, 1995.
117.
MarshallKA, ReiterRJ, PoeggelerB, AruomaOl, HalliwellB.Evaluation of the antioxidant activity of melatonin in vitro.Free Radic Biol Med21: 307–315, 1996.
118.
LivreaMA, TesoriereL, D'ArpaD, MorrealeM.Reaction of melatonin with lipoperoxyl radicals in phospholipid bilayers. Free Radic Biol Med23: 706–711, 1997.
119.
ReiterRJ. Antioxidant actions of melatonin. Adv Pharmacol38: 103–117, 1997.
120.
ReiterRJ, TanDX, CabreraJ, D'ArpaD, SainzRM, MayoJC, RamosS.The oxidant/antioxidant network: Role of melatonin. Biol Signals Recept8: 56–63, 1999.
121.
CagnoliCM, AtabayC, KharlamovE, ManevH.Melatonin protects neurons from singlet oxygen-induced apoptosis. J Pineal Res18: 222–226, 1995.
122.
GiladE, CuzzocreaS, ZingarelliB, SalzmanAL, SzaboC.Melatonin is a scavenger of peroxynitrite. Life Sci60: PL169–PL174, 1997.
123.
CuzzocreaS, ZingarelliB, GiladE, HakeP, SalzmanAL, SzaboC.Protective effect of melatonin in carrageenan-induced models of local inflammation: Relationship to its inhibitory effect on nitric oxide production and its peroxynitrite scavenging activity. J Pineal Res23: 106–116, 1997.
124.
NodaY, MoriA, LiburdyR, PackerL.Melatonin and its precursors scavenge nitric oxide. J Pineal Res27: 159–163, 1999.
125.
PoeggelerB, SaarelaS, ReiterRJ, TanDX, ChenLD, ManchesterLC, Barlow-WaldenLR. Melatonin—a highly potent endogenous radical scavenger and electron donor: New aspects of the oxidation chemistry of this indole assessed in vitro.Ann N Y Acad Sci738: 419–420, 1994.
126.
MahalHS, SharmaHS, MukherjeeT.Antioxidant properties of melatonin: A pulse radiolysis study. Free Radic Biol Med26: 557–565, 1999.
127.
ReiterRJ. Oxidative processes and antioxidative defense mechanisms in the aging. FASEB J9: 526–533, 1995.
128.
ReiterRJ. Oxidative damage in the central nervous system: Protection by melatonin. Prog Neurobiol56: 359–384, 1998.
PablosMI, ChuangJI, ReiterRJ, OrtizGG, DanielsWMU, SewerynekE, MelchiorriD, PoeggelerB.Time course of melatonin-induced increase in glutathione peroxidase activity in chick tissues. Biol Signals4: 325–330, 1995.
133.
PablosMI, GuerreroJM, OrtizGG, AgapitoMT, ReiterRJ. Both melatonin and a putative nuclear melatonin receptor agonist CGP 52608 stimulate glutathione peroxidase and glutathione reductase activities in mouse brain in vivo.Neuroendocrinol Lett18: 49–58, 1997.
134.
PablosMI, ReiterRJ, OrtizGG, AgapitoMT, ChuangJI, SewerynekE.Rhythms of glutathione peroxidase and glutathione reductase in the brain of chick and their inhibition by light. Neurochem Int32: 69–75, 1998.
135.
SewerynekE, ReiterRJ, MelchiorriD, OrtizGG, LewinskiA.Oxidative damage in the liver induced by ischemia-reperfusion: Protection by melatonin. Hepatogastroenterology43: 898–903, 1996.
136.
PierreficheG, LaboritH.Oxygen radicals, melatonin, and aging. Exp Gerontol30: 213–227, 1995.
137.
UrataY, HonmaS, GotoS, TodorokiS, IidaT, ChoS, HonmaK, KondoT.Melatonin induces γ-glutamylcysteine synthetase mediated by activator protein-1 in human vascular endothelial cells. Free Radic Biol Med27: 838–847, 1999.
138.
MontillaP, TunezI, MunozMC, SoriaJV, LopezA.Antioxidative effect of melatonin in rat brain oxidative stress induced by adriamycin. Rev Esp Fisiol53: 301–305, 1997.
139.
BettahiI, PozoD, OsunaC, ReiterRJ, Acuna-CastroviejoD, GuerreroJM. Physiological concentrations of melatonin inhibit nitric oxide synthase activity in the rat hypothalamus. J Pineal Res20: 205–210, 1996.
140.
GuerreroJM, ReiterRJ, OrtizGG, PablosMI, SewerynekE, ChuangJI. Melatonin prevents increases in neural nitric oxide and cycle GMP production after transient brain ischemia and reperfusion in the Mongolian gerbil (Meriones unguiculalus). J Pineal Res23: 24–31, 1997.
141.
PozoD, ReiterRJ, CalvoJM, GuerreroJM. Inhibition of cerebellar nitric oxide synthase and cyclic GMP production by melatonin via complex formation with calmodulin. J Cell Biochem65: 430–4421997.
142.
WaldhauserF, DietzelM.Daily and annual rhythms in human melatonin secretion: Role in puberty control. Ann N Y Acad Sci453: 205–214, 1985.
143.
TanD-X, ReiterRJ, ChenLD, PoeggelerB, ManchesterLC, Barlow-WaldenLR. Both physiological and pharmacological levels of melatonin reduce DNA adduet formation induced by the carcinogen safrole. Carcinogenesis15: 215–218, 1994.
144.
ManevH, UzT, KharlamovA, JooJJ. Increased brain damage after stroke or excitotoxic seizures in melatonin-deficient rats. FASEB J10: 1546–1551, 1996.
145.
AntolinI, ObstB, BurkhardtS, HardelandR.Antioxidative protection in a high-melatonin organism: The dinoflagellate Gonyaulax polyedra is rescued from lethal oxidative stress by strongly elevated, but physiologically possible concentrations of melatonin. J Pineal Res23: 182–190, 1997.
146.
ReiterRJ, TanD-x, KimSJ, ManchesterLC, QiW, GarciaJJ, CabreraJC, El-SokkaryG, Rouvier-GarayV.Augmentation of indices of oxidative damage in life-long melatonin-deficient rats. Mech Aging Dev110: 157–173, 1999.
ReiterRJ, CraftCM, JohnsonJEJr., KingTS, RichardsonBA, VaughanGM, VaughanMKAge-associated reduction in nocturnal melatonin levels in female rats. Endocrinology109:1295–12971981.
149.
ReiterRJ. Pineal melatonin: Cell Biology of its synthesis and of its physiological interactions. Endocr Rev12: 151–180, 1991.
150.
BenotS, MolineroP, SouttoM, GobemaR, GuerreroJM. Circadian variations in the rat serum total antioxidant status: Correlation with melatonin levels. J Pineal Res25: 1–4, 1998.
151.
BenotS, GobernaR, ReiterRJ, Garcia-MaurinoS, OsunaC, GuerreroJM. Physiological levels of melatonin contribute to the antioxidant capacity of human serum. J Pineal Res27: 59–64, 1999.
152.
RodriguezAB, MarchenaJM, NogalesG, DuranJ, BarrigaC.Correlation between the circadian rhythm of melatonin, phagocytosis, and superoxide anion levels in ring dove heterophils. J Pineal Res26: 35–42, 1999.
153.
SainzRM, MayoJC, UriaH, KotierM, AntolinI, RodriguezC, Menendez-PelaezA.The pineal neurohormone melatonin prevents in vivo and in vitro apoptosis in thymocytes. J Pineal Res19: 178–1881995.
154.
MaestroniGJM, CovacciV, ContiA.Hematopoietic rescue via T-cell dependent, endogenous granulocyte-macrophage colony-stimulating factor induced by the pineal neurohormone melatonin in tumor-bearing mice. Cancer Res54: 2429–2432, 1994.
155.
RuifrokACC, WeilMM, ThamesHD, MasonKA. Diurnal variations in the expression of radiation-induced apoptosis. Radiat Res149: 360–365, 1998.
156.
TanD-X, PoeggelerB, ReiterRJ, ChenLD, ChenS, ManchesterLC, Barlow-WaldenLR. The pineal hormone melatonin inhibits DNA-adducts formation induced by the chemical carcinogen safrole in vivo.Cancer Lett70: 65–71, 1993.
157.
ReiterRJ, TangL, GarciaJJ, Munoz-HoyosA.Pharmacological actions of melatonin in free radical pathophysiology. Life Sci60: 2255–2271, 1997.
158.
TangL, ReiterRJ, LiZR, OrtizGG, YuBP, GarciaJJ. Melatonin reduces the increase in 8-hydroxydeoxyguanosine levels in the brain and liver of kainic acid treated rats. Mol Cell Biochem178: 299–3031998.
159.
MoriokaN, OkataniY, WakatsukiA.Melatonin protects against age-related DNA damage in the brains of female senescence-accelerated mice. J Pineal Res27: 202–209, 1999.
160.
QiW, ReiterRJ, TanDX, ManchesterLC, KimSJ, GarciaJJ. Inhibitory effects of melatonin on ferric nitriloriacetate-induced lipid peroxidation and oxidative DNA damage in the rat kidneyToxicology139:81–91, 1999.
161.
QiW, ReiterRJ, TanDX, GarciaJJ, ManchesterLC, KarbownikM, CalvoJR. Chromium (III)-induced 8-hydroxydeoxyguanosine in DNA and its reduction by antioxidants: Comparative effects of melatonin, ascorbate, and vitamin E. Environ Health Persoect108: 399–402, 2000.
162.
ReiterRJ, MelchiorriD, SewerynekE, PoeggelerB, Barlow-WaldenL, ChuangJ, OrtizGG, Acuna-CastroviejoD.A review of the evidence supporting melatonin's role as an antioxidant. J Pineal Res18: 1–11, 1995.
163.
PrincFG, MaxitAG, CardaldaC, BattleA, JuknatAA. In vivo protection by melatonin against 8-aminolevulinic acid-induced oxidative damage and its antioxidant effect on the activity of haem enzymes. J Pineal Res24: 1–8, 1998.
164.
SiuAW, ReiterRJ, ToCH. Pineal indolamines and vitamin E reduce nitric oxide-induced lipid peroxidation in rat retinal homogenates. J Pineal Res27: 122–128, 1999.
165.
TesoriereL, D'ArpaD, ContiS, GiaconeV, PintandiAM, LivreaMA. Melatonin protects human red blood cells from oxidative hemolysis: New insight into the radical-scavenging activity. J Pineal Res27: 95–105, 1999.
166.
MusatovSA, AnisimovVN, AndreV, VigreuxC, GodardT, GauduchonP, SichelF.Modulatory effects of melatonin on genotoxic response of reference mutagens in the Ames test and the comet assay. Mutat Res417: 75–84, 1998.
Vijayalaxmi MeltzML, ReiterRJ, HermanTS, KumarSK. Melatonin and protection from whole-body irradiation: Survival studies in mice. Mutat Res425: 21–27, 1999.
169.
KayaH, DelibasN, SerteserM, UlukayaE, OzkayaO.The effect of melatonin on lipid peroxidation during radiotherapy in female rats. Strahlenther Onkol175: 285–288, 1999.
170.
AhlersI, SolarP, AhlersovaE, KassayovaM, SmajdaB.The influence of melatonin on metabolic changes in female rats induced by continuous irradiation and/or administration of 7,12-dimethylbenz/a/anthracene. Neoplasma44: 253–257, 1997.
171.
Vijayalaxmi MeltzML, ReiterRJ, HermanTS. Melatonin and protection from genetic damage in blood and bone marrow: Whole-body irradiation studies in mice. J Pineal Res27: 221–225, 1999.
172.
BadrFM, El HabitOHM, HarrazMM. Radioprotective effect of melatonin assessed by measuring chromosomal damage in mitotic and meiotic cells. Mutat Res444: 367–372, 1999.
173.
MohanN, SadeghiK, ReiterRJ, MeltzML. The neurohormone melatonin inhibits cytokine, mitogen, and ionizing radiation-induced NF-κB. Biochem Mol Biol Int37: 1063–1070, 1995.
174.
KundurovicZ, ScepovicM.Histoenzymological reactions of the thyroid gland in irradiated and previously melatonin-treated irradiated rats. Acta Med Iugosl43: 337–347, 1989.
175.
KundurovicZ, MornjakovicZ.Morphometric characteristics of thyroid cells in irradiation-stressed rats treated with pinealectomy and melatonin. Med Arh46: 9–10, 1992.
176.
MornjakovicZ, ScepovicM, KundurovicZ.Morphometric aspects of seminiferous tubules in rats treated with melatonin and whole body irradiation. Med Arh45: 9–10, 1991.
177.
MornjakovicZ, AlicelebicS, BilalovicN, SuskoI.Morphometric characteristics of Leydig cells after total irradiation of rats treated with melatonin. Med Arh52: 183–184, 1998.
178.
JahnkeG, MarrM, MyersC, WilsonR, TravlosG, PriceC.Maternal and developmental toxicity evaluation of melatonin administered orally to pregnant Sprague-Dawley rats. Toxicol Sci50: 271–279, 1999.
179.
BarchasJ, DaCostaF, SpectorS.Acute pharmacology of melatonin. Nature (London)214: 919–921, 1967.
180.
IshizukaB, KuribayashiY, MuraiK, AmemiyaA, ItohMT. The effect of melatonin on in vitro fertilization and embryo development in mice. J Pineal Res28: 48–51, 2000.
181.
LiebermanHR, WaldhauserF, GarfieldG, LynchHJ, WurtmanRJ. Effects of melatonin on mood and performance. Brain Res323: 201–207, 1984.
182.
ArendtM, AldhousM, MarksV.Alleviation of jet lag by melatonin: Preliminary results of controlled double-blind trial. Br Med J Clin Res292: 1170, 1986.
183.
LissoniP, BamiS, CrispinoS, TanciniG, FraschiniF.Endocrine and immune effects of melatonin therapy in metastatic cancer patients. Eur J Cancer Clin Oncol25: 789–795, 1989.
SarnelA, WegmannAM, VejvodaM, MaassH, GundelA, SchutzM.Influence of melatonin treatment on human circadian rhythmicity before and after a simulated 9-hour time shift. J Biol Rhythms6: 235–248, 1991.
186.
VoordouwBC, EuserR, VerdonkRE, AlberdaBT, de JongFH, DrogendijkAC, FauserBC, CohenM.Melatonin and melatonin-progestin combinations alter pituitary-ovarian function and can inhibit ovulation. J Clin Endocrinol Metab74: 108–117, 1992.
187.
LissoniP, BamiS, RovelliF, BrivioF, AdrizzoiaA, TanciniG, ContiA, MaestroniGJ. Neuroimmunotherapy of advanced solid neoplasm with single evening subcutaneous injection of low-dose interleukin-2 and melatonin: Preliminary results. Eur J Cancer29: 185–189, 1993.
188.
NordlundJJ, LernerAB. The effects of oral melatonin on skin color and on the release of pituitary hormones. J Clin Endocrinol Metab45: 768–774, 1977.
189.
BarsacchiR, KusmicC, DamianiE, CarloniP, GreciL, DonatoL.Vitamin E consumption induced by oxidative stress in red blood cells is enhanced by melatonin and reduced by N-acetyl-serotonin. Free Radic Biol Med24: 1187–1192, 1998.
190.
MarchiafavaPL, LongoniB.Melatonin as an antioxidant in retinal photoreceptors. J Pineal Res26: 184–189, 1999.
