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Analysis of N1-acetyl-N2-formyl-5-methoxykynuramine/N1-acetyl-5-methoxy-kynuramine formation from melatonin in mice

Authors

  • Sida Niu,

    1. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, KS, USA
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    • Sida Niu and Feng Li contribute equally to this study.

    • Present address: School of Engineering, University of Kansas.

  • Feng Li,

    1. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, KS, USA
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    • Sida Niu and Feng Li contribute equally to this study.

  • Dun-Xian Tan,

    1. Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA
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  • Lirong Zhang,

    1. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, KS, USA
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    • Present address: Department of Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, China.

  • Jeffrey R. Idle,

    1. Institute of Pharmacology, 1st Faculty of Medicine, Charles University, Praha, Czech Republic
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  • Frank J. Gonzalez,

    1. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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  • Xiaochao Ma

    1. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, KS, USA
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  • This work was supported by the National Institutes of Health National Center for Research Resources [COBRE 5P20-RR021940]. Jeffrey R. Idle is grateful to US Smokeless Tobacco Company for a collaborative research grant.

Address reprint requests to Dr. Xiaochao Ma, Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 4089 KLSIC, MS 1018, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA.
E-mail: xma2@kumc.edu

Abstract

Abstract:  The interactions of melatonin, a potent endogenous antioxidant, with reactive oxygen species generate several products that include N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-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.

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