{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T20:12:46Z","timestamp":1790885566656,"version":"4.1.0"},"reference-count":42,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2019,6,24]],"date-time":"2019-06-24T00:00:00Z","timestamp":1561334400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and objectives: toxic liver injury results in nitrooxidative stress. Melatonin is a potent free radical scavenger, an inducible nitric oxide synthase (iNOS) inhibitor and an activator of antioxidant enzymes. The aim of this study was to investigate the hepatoprotective effect of exogenous melatonin on animals with acute toxic hepatitis. Material and methods: 36 healthy Sprague-Dawley male rats were split into three equal groups and given carbon tetrachloride (CCl4), 2 g\/kg (CCl4 group) or the same dose of CCl4 and melatonin, 10 mg\/kg (CCl4\/melatonin group) or saline (control group). The effect of melatonin on prooxidant and antioxidant system indexes, NO and NOS levels in serum and liver, data of mitochondrial chain functions and cytolysis in liver were evaluated in all three groups. Results: melatonin significantly decreased activities of AST, ALT, ceruloplasmine and thiobarbituric acid reactive substance (TBARS) in serum. Catalase activity was lowered in serum but not in the liver. Hepatic TBARS, lipid hydroperoxides and glutathione concentrations were decreased, while superoxide dismutase, mitochondrial cytochrome oxidase and succinate dehydrogenase activities increased. Melatonin inhibited synthesis of stable NO metabolites in serum: NO2-by 37.9%; NO3-by 29.2%. There was no significant difference in content NO2-in the liver, but concentration of NO3-increased by 32.6%. Melatonin significantly reduced iNOS concentrations both in serum (59.7%) and liver (57.8%) but did not affect endothelial isoform enzyme activities neither in serum, nor in liver. The histopathological liver lesions observed in the CCl4\/melatonin group were less severe than those seen in the CCl4 group. Conclusions: we demonstrated an ameliorating effect of melatonin on prooxidants and antioxidants, NO-NOS systems balance, mitochondrial function and histopathological lesions in the liver in rats with CCl4-induced hepatitis.<\/jats:p>","DOI":"10.3390\/medicina55060304","type":"journal-article","created":{"date-parts":[[2019,6,24]],"date-time":"2019-06-24T16:52:51Z","timestamp":1561395171000},"page":"304","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Hepatoprotective Effect of Melatonin in Toxic Liver Injury in Rats"],"prefix":"10.3390","volume":"55","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1491-1935","authenticated-orcid":false,"given":"Oleksandra","family":"Oleshchuk","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Clinical Pharmacology, I. Horbachevsky Ternopil State Medical University, Maidan Voli sq. 1, 46001 Ternopil, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yana","family":"Ivankiv","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Clinical Pharmacology, I. Horbachevsky Ternopil State Medical University, Maidan Voli sq. 1, 46001 Ternopil, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Halina","family":"Falfushynska","sequence":"additional","affiliation":[{"name":"Department of orthopedagogy and physical therapy, Ternopil V. Hnatiuk National Pedagogical University, Maxym Kryvonis str. 2, 46027 Ternopil, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3219-931X","authenticated-orcid":false,"given":"Alla","family":"Mudra","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, I. Horbachevsky Ternopil State Medical University, Maidan Voli sq 1., 46001 Ternopil, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1321-5679","authenticated-orcid":false,"given":"Nataliya","family":"Lisnychuk","sequence":"additional","affiliation":[{"name":"Central Scientific Research Laboratory, I. Horbachevsky Ternopil State Medical University, Maidan Voli sq. 1, 46001 Ternopil, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,6,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1034\/j.1600-079X.2003.02111.x","article-title":"Melatonin: A hormone, a tissue factor, an autocoid, a paracoid and an antioxidant vitamin","volume":"34","author":"Tan","year":"2003","journal-title":"J. Pineal Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/S1521-690X(03)00016-2","article-title":"Melatonin: Clinical relevance","volume":"17","author":"Reiter","year":"2003","journal-title":"Best Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1600-079X.1993.tb00503.x","article-title":"Melatonin and sleep in humans","volume":"15","author":"Dawson","year":"1993","journal-title":"J. Pineal Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18388\/abp.2007_3264","article-title":"Melatonin and its metabolites: New findings regarding their production and their radical scavenging actions","volume":"54","author":"Reiter","year":"2007","journal-title":"Acta Biochim. Pol."},{"key":"ref_5","first-page":"270","article-title":"Melatonin receptors","volume":"Volume 2","author":"Girdlestone","year":"2000","journal-title":"The IUPHAR Compendium of Receptor Characterization and Classification"},{"key":"ref_6","first-page":"19","article-title":"Melatonin in Humans","volume":"57","author":"Karasek","year":"2006","journal-title":"J. Physiol. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/0197-0186(95)80002-3","article-title":"The role of the neurohormone melatonin as a buffer against macromolecular oxidative damage","volume":"27","author":"Reiter","year":"1995","journal-title":"Neurochem. Int."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1056\/NEJM199701163360306","article-title":"Melatonin in humans","volume":"336","author":"Brzezinski","year":"1997","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1136\/thx.2004.038471","article-title":"Nitric oxide, hypoxia, and superoxide: The good, the bad, and the ugly!","volume":"60","author":"Dweik","year":"2005","journal-title":"Thorax"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1034\/j.1600-0676.2001.021003161.x","article-title":"Nitric oxide in the liver","volume":"21","author":"Moore","year":"2001","journal-title":"Liver"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1089\/152308601300185214","article-title":"Prooxidant and antioxidant function of nitric oxide in liver toxicity","volume":"3","author":"Laskin","year":"2001","journal-title":"Antioxid. Redox Signal."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1007\/s13105-014-0322-7","article-title":"Hepatoprotective effects of melatonin against pronecrotic cellular events in streptozotocin-induced diabetic rats","volume":"70","author":"Grigorov","year":"2014","journal-title":"J. Physiol. Biochem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1021\/acs.chemrestox.8b00216","article-title":"Design, Synthesis, and Biological Activity of Hydrogen Peroxide Responsive Arylboronate Melatonin Hybrids","volume":"32","author":"Bedini","year":"2019","journal-title":"Chem. Res. Toxicol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1034\/j.1600-079X.2003.00043.x","article-title":"Melatonin prevents methotrexate-induced hepatorenal oxidative injury in rats","volume":"34","author":"Jahovic","year":"2003","journal-title":"J. Pineal Res."},{"key":"ref_15","first-page":"41","article-title":"Modification of the method for determining lipid peroxide in the test with thiobarbituric acid","volume":"11","author":"Andreeva","year":"1988","journal-title":"Lab. Delo"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/0003-2697(82)90118-X","article-title":"Analysis of nitrate, nitrite and [15N] nitrate in biological fluids","volume":"126","author":"Green","year":"1982","journal-title":"Anal. Biochem."},{"key":"ref_17","first-page":"16","article-title":"Method for determination of catalase activity","volume":"1","author":"Korolyuk","year":"1988","journal-title":"Lab. Delo"},{"key":"ref_18","unstructured":"Kolb, V.G., and Kamyshnikov, V.S. (1982). Handbook of Clinical Chemistry."},{"key":"ref_19","first-page":"678","article-title":"The role of superoxide dismutase in oxidative processes in cells and the method of its determination in biological materials","volume":"11","author":"Chevari","year":"1985","journal-title":"Lab. Delo"},{"key":"ref_20","first-page":"33","article-title":"Spectrophotometric determination of lipid hydroperoxide in the blood plasma","volume":"3","author":"Gavrilov","year":"1983","journal-title":"Lab. Delo"},{"key":"ref_21","unstructured":"Orekhovich, V.N. (1977). Modern Methods in Biochemistry, AMS USSR Moscow, Medicine."},{"key":"ref_22","unstructured":"Eshchenko, N.D., and Volsky, G.G. (1982). Determination of the amount of succinic acid and succinate dehydrogenase activity. Methods of Biochemical Researches, Publishing House of Leningrad University."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/0003-9861(59)90090-6","article-title":"Tissue sulfhydryl groups","volume":"82","author":"Ellman","year":"1959","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"11973","DOI":"10.1002\/jcb.28481","article-title":"Adverse impact of carbon tetrachloride on metabolic function in mice","volume":"120","author":"Liang","year":"2019","journal-title":"J. Cellul. Biochem."},{"key":"ref_25","unstructured":"(2019). Containment Levels for Chemical Administration in Animals, Agreement of Boston University Environmental Health and Safety."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/S0016-5085(99)70565-2","article-title":"Nitric oxide increase hepatic arterial blood flow in rats with carbon tetrachloride-induced acute hepatic injury","volume":"117","author":"Tanaka","year":"1999","journal-title":"Gastroenterology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1016\/S0024-3205(01)00935-3","article-title":"Mechanisms involved in gastric protection of melatonin against oxidant stress by ischemia-reperfusion in rats","volume":"68","author":"Cabeza","year":"2001","journal-title":"Life Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/S0024-3205(97)00008-8","article-title":"Melatonin is a scavenger of peroxynitrite","volume":"60","author":"Gilad","year":"1997","journal-title":"Life Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1515\/znc-2001-7-826","article-title":"Mechanism of carbon tetrachloride-induced hepatotoxicity. Hepatocellular damage by reactive carbon tetrachloride metabolites","volume":"56","author":"Boll","year":"2001","journal-title":"Z. Naturforsch C"},{"key":"ref_30","unstructured":"Hubsky, Y.I. (1989). Correction of the chemical liver injury. The Health."},{"key":"ref_31","first-page":"803","article-title":"Hepatoprotective effect of trimethylgallic acid esters against carbon tetrachloride-induced liver injury in rats","volume":"53","author":"Sachdeva","year":"2015","journal-title":"J. Exp. Biol."},{"key":"ref_32","first-page":"43","article-title":"Role of the antioxidant system in the pathogenesis of toxic hepatitis","volume":"2","author":"Gonskii","year":"1996","journal-title":"Patol. Fiziol. Eksp Ter."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s10863-008-9125-2","article-title":"Hepatocyte mitochondrion electron-transport chain alterations in CCl4 and alcohol induced hepatitis in rats and their correction with simvastatin","volume":"40","author":"Shiryaeva","year":"2008","journal-title":"J. Bioenerg. Biomemb."},{"key":"ref_34","first-page":"10","article-title":"Melatonin as hepatoprotector at diabetes","volume":"1","author":"Oleshchuk","year":"2015","journal-title":"Bull. Sci. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"39","DOI":"10.11603\/mcch.2410-681X.2015.v17.i2.4867","article-title":"Indicators of prooxidant-antioxidant homeostasis of healthy animals under the introduction of melatonin","volume":"17","author":"Ivankiv","year":"2015","journal-title":"Med. Clin. Chem."},{"key":"ref_36","first-page":"791","article-title":"Role of endogenous melatonin and its MT2 receptor in the modulation of caerulein-induced pancreatitis in the rats","volume":"53","author":"Jaworek","year":"2002","journal-title":"J. Physiol. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1007\/BF03345555","article-title":"Melatonin and nitric oxide","volume":"29","author":"Aydogan","year":"2006","journal-title":"J. Endocrinol. Investig."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1111\/jpi.12196","article-title":"Melatonin and its metabolites as copper chelating agents and their role in inhibiting oxidative stress: A physicochemical analysis","volume":"58","author":"Galano","year":"2015","journal-title":"J. Pineal Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1111\/j.1600-079X.1998.tb00361.x","article-title":"The interaction of melatonin and its precursors with aluminium, cadmium, copper, iron, lead, and zinc: An adsorptive voltammetric study","volume":"24","author":"Limson","year":"1998","journal-title":"J. Pineal Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1002\/iub.1613","article-title":"The role of insufficient copper in lipid synthesis and fatty-liver disease","volume":"69","author":"Morrell","year":"2017","journal-title":"IUBMB Life"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1111\/jgh.14104","article-title":"Prediction of carotid intima\u2013media thickness in obese patients with low prevalence of comorbidities by serum copper bioavailability","volume":"33","author":"Tarantino","year":"2018","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"133","DOI":"10.2174\/1568026023394344","article-title":"Melatonin, mitochondria homeostasis and mitochondrial-related diseases","volume":"2","author":"Escames","year":"2002","journal-title":"Curr. Top. Med. Chem."}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/55\/6\/304\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:00:53Z","timestamp":1760187653000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/55\/6\/304"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6,24]]},"references-count":42,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2019,6]]}},"alternative-id":["medicina55060304"],"URL":"https:\/\/doi.org\/10.3390\/medicina55060304","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,6,24]]}}}