The permeability and cytotoxicity of insulin-mimetic vanadium compounds.
OBJECTIVE
The aim of this study was to investigate the mechanism of permeation and cytotoxicity of vanadium compounds, [VO(acac)2], [VO(ma)2], and vanadate.


METHODS
Absorptive transport were carried out in Caco-2 monolayers grown on transwell inserts. Vanadium was quantified using inductively coupled plasma atomic emission spectrometry (ICP-AES). The change of Caco-2 cells in the microvilli morphology and F-actin structure was visualized by transmission electron microscopy and confocal laser scanning microscopy.


RESULTS
The three vanadium compounds were taken up by Caco-2 cells via simple passive diffusion. [VO(acac)2] were mainly transcellularly transported and exhibited the highest apparent permeabilty coefficients (8.2 x 10(-6) cm(-1)). The cell accumulation of [VO(acac)2] was found to be greater than that of [VO(ma)2], and vanadate caused much less accumulation than the other two compounds. Vanadium compounds induced intracellular reactive oxygen species, reduced the transepithelial electric resistance, caused morphological change in microvilli, and led to different perturbation of F-actin structure.


CONCLUSIONS
The three compounds exhibited different permeability due to different diffusion process and cellular uptake. The toxicity of vanadium complexes on Caco-2 monolayer involved F-actin-related change of tight junction and impairment of microvilli. The toxicity was also related to elevated intracellular reactive oxygen species (ROS) and their cellular accumulation.
Yang
Xiao-Gai
XG
Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100083, China. xyang@bjmu.edu.cn
Yang
Xiao-Da
XD
Yuan
Lan
L
Wang
Kui
K
Crans
Debbie C
DC
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000199:Actins / Q000187:drug effects; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D002681:China; D004058:Diffusion / Q000187:drug effects; D017097:Electric Impedance; D005562:Formazans; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D006885:Hydroxybutyrates; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics; D018613:Microscopy, Confocal / Q000379:methods; D008855:Microscopy, Electron, Scanning / Q000379:methods; D008871:Microvilli / Q000187:drug effects; D010422:Pentanones; D011753:Pyrones; D017382:Reactive Oxygen Species / Q000009:adverse effects / Q000378:metabolism; D013054:Spectrophotometry, Atomic / Q000379:methods; D013481:Superoxides; D013778:Tetrazolium Salts; D014638:Vanadates; D017968:Vanadium Compounds / Q000009:adverse effects* / Q000737:chemistry / Q000145:classification
D000199:Actins; D005562:Formazans; D006885:Hydroxybutyrates; D007004:Hypoglycemic Agents; D010422:Pentanones; D011753:Pyrones; D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts; D017968:Vanadium Compounds; D013481:Superoxides; C049529:acetyl acetonate; C079782:MTT formazan; C074212:bis(maltolato)oxovanadium(IV); D014638:Vanadates; D006861:Hydrogen Peroxide; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid