AUTHOR=Tian Xiangge , Kang Xiaohui , Yan Fei , Feng Lei , Huo Xiaokui , Zhang Houli , Wang Yan , Lv Xia , Ma Xiaochi , Yuan Jinsong , Peng Jiao , Dai Li 

TITLE=ROS-dependent catalytic mechanism of melatonin metabolism and its application in the measurement of reactive oxygen

JOURNAL=Frontiers in Chemistry

VOLUME=Volume 11 - 2023

YEAR=2024

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2023.1229199

DOI=10.3389/fchem.2023.1229199

ISSN=2296-2646

ABSTRACT=Melatonin (Mel) is an endogenous active molecule whose metabolism progress significantly influence its bioactivity. However, the detailed metabolic pathway of Mel in the pathological state has not yet been fully illustrated. In this study, 16 metabolites of Mel in cancer cells and human liver microsomes were identified, of which, seven novel metabolites were newly discovered. Among them, 2-hydroxyl-melatonin (2-O-Mel) as the major metabolite in cancer cells was revealed for the first time, which was different from the metabolite found in human liver. Furthermore, CYP1A1/1A2 and reactive oxygen species (ROS) mediated 2-hydroxylation reactions of Mel were verified to be the two metabolic pathways in liver and cancer cells, respectively. ROS-dependent formation of 2-O-Mel was the major pathway in cancer cells. Furthermore, the underlying catalytic mechanism of Mel to 2-O-Mel in the presence of ROS was fully elucidated by computational chemistry analysis. Therefore, the generation of 2-O-Mel from Mel could serve as another index for the endogenous reactive oxygen level. Finally, based on the ROS-dependent production of 2-O-Mel, Mel was successfully used for detecting the oxygen carrying capacity of hemoglobin in human blood. Our investigation further enriched the metabolic pathway of Mel, especially for the ROS-dependent formation of 2-O-Mel that serves as a diagnostic and therapeutic target for the rational use of Mel in clinic.