title: Analysis of N1-acetyl-N2-formyl-5-methoxykynuramine/N1-acetyl-5-methoxy-kynuramine formation from melatonin in mice.
abstract: The interactions of melatonin, a potent endogenous antioxidant, with reactive oxygen species generate several products that include N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (AFMK) and N(1)-acetyl-5-methoxy-kynuramine (AMK). The physiological or pathological significance of AFMK/AMK formation during the process of melatonin metabolism in mammals has not been clarified. Using a metabolomic approach in the current study, the AFMK/AMK pathway was thoroughly investigated both in mice and humans. Unexpectedly, AFMK and AMK were not identified in the urine of humans nor in the urine, feces or tissues (including liver, brain, and eyes) in mice under the current experimental conditions. Metabolomic analysis did identify novel metabolites of AMK, i.e. hydroxy-AMK and glucuronide-conjugated hydroxy-AMK. These two newly identified metabolites were, however, not found in the urine of humans. In addition, oxidative stress induced by acetaminophen in the mouse model did not boost AFMK/AMK formation. These data suggest that AFMK/AMK formation is not a significant pathway of melatonin disposition in mice, even under conditions of oxidative stress.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Sida
authors.initials: S
authors.lastname: Niu
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Dun-Xian
authors.initials: DX
authors.lastname: Tan
authors.forename: Lirong
authors.initials: L
authors.lastname: Zhang
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Idle
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Xiaochao
authors.initials: X
authors.lastname: Ma
mesh_terms: D000082:Acetaminophen / Q000633:toxicity; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D006801:Humans; D007735:Kynuramine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000652:urine; D008297:Male; D008550:Melatonin / Q000737:chemistry / Q000378:metabolism*; D053858:Metabolic Networks and Pathways / Q000502:physiology; D055442:Metabolome; D055432:Metabolomics / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D025341:Principal Component Analysis
chemical_list: D000975:Antioxidants; D000082:Acetaminophen; D007735:Kynuramine; C041550:N-acetyl-N-formyl-5-methoxykynurenamine; C032131:N-acetyl-5-methoxy kynurenamine; D008550:Melatonin