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Over the years, DNA damage has been suggested to be directly linked to mutagenesis, carcinogenesis and ageing. There is ample evidence suggesting that considerable DNA damage may be induced by metabolites produced during normal or aberrant metabolic processes. Herein, we examine the chemical basis of cytotoxicity of some endogenous metabolites. Towards this goal, we study the DNA reactive activities of the neurotransmitter serotonin and its structural analogues tryptophan and melatonin in the presence of copper. Fluorescence spectroscopy reveals a simple mode of interaction of these metabolites with calf thymus DNA and copper ions. The results of agarose gel electrophoresis demonstrate copper mediated strand scission in plasmid pBR322 DNA by these metabolites. Further, the relative DNA binding affinity order was affirmed using molecular docking studies involving the interaction of these metabolites with calf thymus DNA. We employ single cell alkaline gel electrophoresis and determine the relative efficiency of cellular DNA breakage as Serotonin>Melatonin>Tryptophan. We hypothesize that such cellular DNA breakage is mediated by mobilization of copper ions bound to chromatin. Consistent with previous observations that many known antioxidants of plant and animal origin also exhibit prooxidant properties, these metabolites might contribute to oxidative DNA breakage in the presence of redox active metals such as copper. Our findings reveal a putative mechanism by which some endogenous metabolites may cause DNA damage leading to mutations and genetic diseases.

DNA Binding and its Degradation by the Neurotransmitter Serotonin and its Structural Analogues Melatonin and Tryptophan: Putative Neurotoxic Mechanism