Alleviation of podophyllotoxin toxicity using coexisting flavonoids from Dysosma versipellis

PLoS One. 2013 Aug 21;8(8):e72099. doi: 10.1371/journal.pone.0072099. eCollection 2013.

Abstract

Podophyllotoxin (POD) is a lignan-type toxin existing in many herbs used in folk medicine. Until now, no effective strategy is available for the management of POD intoxication. This study aims to determine the protective effects of flavonoids (quercetin and kaempferol) on POD-induced toxicity. In Vero cells, both flavonoids protected POD-induced cytotoxicity by recovering alleviating G2/M arrest, decreasing ROS generation and changes of membrane potential, and recovering microtubule structure. In Swiss mice, the group given both POD and flavonoids group had significantly lower mortality rate and showed less damages in the liver and kidney than the group given POD alone. As compared to the POD group, the POD plus flavonoids group exhibited decreases in plasma transaminases, alkaline phosphatase, lactate dehydrogenase, plasma urea, creatinine and malondialdehyde levels, and increases in superoxide dismutase and glutathione levels. Histological examination of the liver and kidney showed less pathological changes in the treatment of POD plus flavonoids group. The protective mechanisms were due to the antioxidant activity of flavonoids against the oxidative stress induced by POD and the competitive binding of flavonoids against POD for the same colchicines-binding sites. The latter binding was confirmed by the tubulin assembly assay in combination with molecular docking analyses. In conclusion, this study for the first time demonstrated that the coexisting flavonoids have great protective effects against the POD toxicity, and results of this study highlighted the great potential of searching for effective antidotes against toxins based on the pharmacological clues.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaline Phosphatase / blood
  • Animals
  • Antioxidants / pharmacology
  • Berberidaceae / chemistry*
  • Cell Survival / drug effects
  • Chlorocebus aethiops
  • Creatinine / blood
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Kaempferols / chemistry
  • Kaempferols / metabolism
  • Kaempferols / pharmacology*
  • Kidney / drug effects
  • Kidney / pathology
  • L-Lactate Dehydrogenase / blood
  • Liver / drug effects
  • Liver / pathology
  • Male
  • Malondialdehyde / blood
  • Mice
  • Microscopy, Fluorescence
  • Models, Molecular
  • Podophyllotoxin / chemistry
  • Podophyllotoxin / metabolism
  • Podophyllotoxin / toxicity*
  • Protein Binding
  • Quercetin / chemistry
  • Quercetin / metabolism
  • Quercetin / pharmacology*
  • Reactive Oxygen Species / metabolism
  • Transaminases / blood
  • Tubulin / chemistry
  • Tubulin / metabolism
  • Urea / blood
  • Vero Cells

Substances

  • Antioxidants
  • Kaempferols
  • Reactive Oxygen Species
  • Tubulin
  • Malondialdehyde
  • kaempferol
  • Urea
  • Quercetin
  • Creatinine
  • L-Lactate Dehydrogenase
  • Transaminases
  • Alkaline Phosphatase
  • Podophyllotoxin

Grants and funding

This project was supported by National Natural Science Foundation of China (21072078), Doctoral Fund of Ministry of Education of China (20114401110005), Guangdong High Level Talent Scheme to RWJ and the Fundamental Research Funds for the Central Universities (21612603 and 21611398). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.