The natural anthraquinones from Rheum palmatum induced the metabolic disorder of melatonin by inhibiting human CYP and SULT enzymes

- The herbs or foods containing abundant anthraquinones such as R. palmatum will cause a metabolic disorder of Mel, and should be avoided to combine application with Mel.
- Five anthraquinones including: aloeemodin (1), rhein (2), emodin (3), chrysophanol (4), and physcion (5) from R. palmatum exhibited significant inhibitory effect on the melatonin metabolism.
- The relationships between compounds' inhibition activities and their structures were also investigated using computational model to further explain the inhibition mechanism.

Melatonin (Mel) as an endogenous hormone, has been widely used in clinic for multiple therapeutic purposes. Further, the natural anthraquinones were widespread in various plants including herbs, foods, and some flavoring agents. The present work aims to evaluate the metabolic disorder of Mel caused by various common herbs and further identify their underlying mechanism. More importantly, the relationships between inhibitory activity and their structures were also investigated. Our results demonstrate that some herbs containing anthraquinone derivatives exhibited strong inhibition on Mel metabolism. Additionally, five anthraquinones from R. palmatum could inhibit phase I and II metabolism of Mel with a mixed inhibition kinetic model based on the mechanism of inhibiting human CYP1A1, 1A2, and SULT1A1. At last, the influence of R. palmatum and its five major components on the Mel metabolism were verified in human primary hepatocytes. In conclusion, our studies elucidated that herbs or foods containing abundant anthraquinones such as R. palmatum will cause a metabolic disorder of Mel, and should be avoided to combined application with Mel in clinic.

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