Cyclic 3-Hydroxymelatonin: A Melatonin Metabolite Generated as a Result of Hydroxyl Radical Scavenging

The pineal secretory product, melatonin, is a potent, endogenous hydroxyl radical (HO⃙) scavenger. When melatonin was incubated in different in vitro cell-free HO⃙-generating systems, a novel melatonin adduct was formed. The molecular weight of this new compound is 248. Its structure was found to be cyclic 3-hydroxymelatonin (3-OHM). A proposed reaction pathway suggests that 3-OHM is the footprint product of the interaction between melatonin with HO⃙. 3-OHM was also detected in the urine of both rats and humans. This urinary metabolite is identical to the compound generated in the in vitro chemical reaction between HO⃙ and melatonin. This provides direct evidence that melatonin, under physiological conditions, functions as an antioxidant to detoxify the most reactive and cytotoxic endogenous HO⃙. When exogenous melatonin was administered to young rats, urinary 3-OHM levels increased significantly in the treated rats compared to those in controls. This indicates that even in young animals there is insufficient endogenously produced melatonin to detoxify the basal levels of the toxic HO⃙. The accumulated damage induced by the escaped HO⃙ that results when the HO⃙ avoids detoxification over the course of a life time may directly or indirectly accelerate aging and aging-related diseases.