Abstract
BackgroundAbnormally elevated xanthine oxidase (XO) activity has been verified to cause various pathological processes, such as gout, oxidative stress injury and metabolic syndrome. Thus, XO activators may exhibit above potential toxicological properties. Plumbagin (PLB) is an important active compound in traditional Chinese medicine (TCM), while its obvious toxic effects have been reported, including diarrhea, skin rashes and hepatic toxicity. However, the potential toxicity associated with enhancement of XO activity has not been fully illuminated so far.MethodsThe present study investigated the effect of PLB on XO activity by culturing mouse liver S9 (MLS9), human liver S9 (HLS9), XO monoenzyme system with PLB and xanthine. Then, the molecular docking and biolayer interferometry analysis were adopted to study the binding properties between PLB and XO. Finally, the in vivo acceleration effect also investigated by injected intraperitoneally PLB to KM mice for 3 days.ResultsPLB could obviously accelerate xanthine oxidation in the above three incubation systems. Both the Vmax values and intrinsic clearance values (CLint, Vmax/Km) of XO in the three incubation systems increased along with elevated PLB concentration. In addition, the molecular docking study and label-free biolayer interferometry assay displayed that PLB was well bound to XO. In addition, the in vivo results showed that PLB (2 and 10 mg/kg) significantly increased serum uric acid levels and enhanced serum XO activity in mice.ConclusionIn summary, this study outlines a potential source of toxicity for PLB due to the powerful enhancement of XO activity, which may provide the crucial reminding for the PLB-containing preparation development and clinical application.
Highlights
Elevated xanthine oxidase (XO) activity has been verified to cause various pathological processes, such as gout, oxidative stress injury and metabolic syndrome
As the final product of the purine compound metabolic pathway, uric acid exists mainly as monosodium urate (MSU) crystallization with low solubility in biological environments, its content rises with elevated activity of XO [5]
Kinetic analyses for the stimulation of uric acid production in mouse liver S9 (MLS9) We first carried out a kinetic analysis of PLB stimulation of uric acid production in the MLS9 system
Summary
Elevated xanthine oxidase (XO) activity has been verified to cause various pathological processes, such as gout, oxidative stress injury and metabolic syndrome. Xanthine oxidase (XO) is a complex metalloflavoprotein enzyme which mainly distributing in the liver and intestine of mammals [1]. It is one of the most important enzymes in nucleic acid metabolism [2] that directly regulates the production of uric acid in vivo [3]. As the final product of the purine compound metabolic pathway, uric acid exists mainly as monosodium urate (MSU) crystallization with low solubility in biological environments, its content rises with elevated activity of XO [5]. When the MSU concentration exceeds the maximum solubility in the body, it precipitates and deposits in the joint cavity, eventually leading to gout, a clinical issue associated with hyperuricaemia [6]
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