title: Melatonin prevents the free radical and MADD metabolic profiles induced by antituberculosis drugs in an animal model.
abstract: The objective was to determine the effect of combined antituberculosis (anti-TB) drug therapy and an antioxidant, melatonin, on the free radical and organic acid profiles in an experimental rat model. A combined anti-TB drug, Rifater, consisting of 12.0 mg rifampicin, 0.8 mg isoniazid, and 23.0 mg pyrazinamide and 18.56 microg melatonin/kg body weight per day (corresponding to average physiological human intake) were orally administered to Sprague-Dawley rats. Hydroxyl radical production was monitored by quantifying 2,3-dihydroxybenzoic acid produced after intraperitonial sodium salicylate injections. Organic acid extractions and gas chromatography-coupled mass spectrometry analyses were performed on collected urine samples. The results show hydroxyl radicals (P = 0.0019) and organic acids (P-value range: 0.037 to <0.001), characteristic of a multiple acyl-CoA dehydrogenase defect (MADD), were elevated with Rifater treatment and these elevations were significantly lowered with melatonin pretreatment (P-value range: 0.031 to <0.001), probably because of its inherent antioxidant activity. We conclude that hydroxyl radical production and an increased organic acid profile induced by anti-TB medication indicates inhibition of the electron transport chain. We also conclude that free radicals leading to clinical symptoms associated with an MADD metabolic profile induced by anti-TB treatment could be alleviated by melatonin intervention.
authors.affiliation: Department of Nutrition, School for Physiology, Nutrition and Consumer Science, North-West University, Potchefstroom, South Africa.
authors.forename: Du Toit
authors.initials: DT
authors.lastname: Loots
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Wiid
authors.forename: Benedict J
authors.initials: BJ
authors.lastname: Page
authors.forename: Lodewyk J
authors.initials: LJ
authors.lastname: Mienie
authors.forename: Paul D
authors.initials: PD
authors.lastname: van Helden
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000378:metabolism; D053418:Death Domain Receptor Signaling Adaptor Proteins; D004338:Drug Combinations; D005609:Free Radicals / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D062385:Hydroxybenzoates / Q000652:urine; D007538:Isoniazid / Q000494:pharmacology; D008550:Melatonin / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D011718:Pyrazinamide / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012293:Rifampin / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D000995:Antitubercular Agents; D002264:Carboxylic Acids; D053418:Death Domain Receptor Signaling Adaptor Proteins; D004338:Drug Combinations; D005609:Free Radicals; D020662:Guanine Nucleotide Exchange Factors; D062385:Hydroxybenzoates; C491370:Madd protein, rat; C087181:isoniazid, pyrazinamide, rifampin drug combination; D011718:Pyrazinamide; C009135:2,3-dihydroxybenzoic acid; D008550:Melatonin; D007538:Isoniazid; D012293:Rifampin