title: Alleviation of podophyllotoxin toxicity using coexisting flavonoids from Dysosma versipellis.
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.
authors.affiliation: Institute of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou, China ; Key Laboratory of Traditional Chinese Medicine Resource and Compound Prescription, Hubei University of Traditional Chinese Medicine, Wuhan, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.forename: Hua
authors.initials: H
authors.lastname: Sun
authors.forename: Lu
authors.initials: L
authors.lastname: Jin
authors.forename: Wei
authors.initials: W
authors.lastname: Cao
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.forename: Chong-Yi
authors.initials: CY
authors.lastname: Guo
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.forename: Wen-Cai
authors.initials: WC
authors.lastname: Ye
authors.forename: Ren-Wang
authors.initials: RW
authors.lastname: Jiang
mesh_terms: D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D028141:Berberidaceae / Q000737:chemistry*; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D003404:Creatinine / Q000097:blood; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D044949:Kaempferols / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D051379:Mice; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D011034:Podophyllotoxin / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D011485:Protein Binding; D011794:Quercetin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000637:Transaminases / Q000097:blood; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D014508:Urea / Q000097:blood; D014709:Vero Cells
chemical_list: D000975:Antioxidants; D044949:Kaempferols; D017382:Reactive Oxygen Species; D014404:Tubulin; D008315:Malondialdehyde; C006552:kaempferol; D014508:Urea; D011794:Quercetin; D003404:Creatinine; D007770:L-Lactate Dehydrogenase; D000637:Transaminases; D000469:Alkaline Phosphatase; D011034:Podophyllotoxin