Characterization of Reaction Products and Mechanisms between Serotonin and Methylglyoxal in Model Reactions and Mice.

Abstract

Serotonin is an important endogenous regulatory neurotransmitter and has also been found in fruits, vegetables, and nuts. Methylglyoxal (MGO) is a reactive dicarbonyl metabolite and also a food toxin that modifies protein and DNA to cause the development of many chronic diseases. The objective of this study is to understand the reaction mechanisms between serotonin and MGO and determine whether serotonin could trap MGO in vivo. Five products were detected in phosphate buffer (pH 7.4) at 37 °C. Four products (compounds 2 and 4-6) were purified from the reaction mixture, and their structures were characterized by the analysis of their high-resolution mass and one- and two-dimensional nuclear magnetic resonance spectra. One product (compound 3), as a result of its instability, could not be properly purified and was tentatively characterized on the basis of its high-resolution mass spectrum and corresponding mass fragments. On the basis of the structures of these five products, two reaction pathways were proposed. Compounds 2, 3, 5, and 6 were produced through the Pictet-Spengler condensation pathway between the primary amine of serotonin and the ketone of MGO, and compound 3 was identified as the intermediate product to form products 2, 5, and 6, whereas compound 4 was formed through nucleophilic substitution by the benzene ring of serotonin, which is a new reaction pathway between biogenic amines and reactive carbonyl species. More importantly, the detection of adducts 2 and 4-6 in mice supports our hypothesis that the reaction between serotonin and MGO also happens in vivo through the same pathways as those in model reactions, suggesting that dietary or endogenous serotonin has the capacity to trap MGO in vivo.