Mechanisms of vanadate-induced cellular toxicity: role of cellular glutathione and NADPH.
Besides its insulin-mimetic effects, vanadate is also known to have a variety of physiological and pharmacological properties, varying from induction of cell growth to cell death and is also a modulator of the multidrug resistance phenotype. However, the mechanisms underlying these effects are still not understood. The present report analyzes the mechanisms of vanadate toxicity in two cell lines previously found to have different susceptibilities to this compound. It was shown that catalase and GSH reversed the sensitivity of a vanadate-sensitive cell line and NADPH sensitized vanadate-resistant cells. NADPH also increased the residues of P-Tyr and the induction of Ras protein expression in vanadate-resistant cells, while GSH avoided these effects in vanadate-sensitive cells. Thus, it seems that the effects of vanadate in signal transduction are dependent on NADPH and are related to cell death. Based on the effects observed in the present study it was suggested that once inside the cell, vanadate is reduced to vanadyl in a process dependent on NADPH. Vanadyl then may react with H2O2 generating primarily peroxovanadium species (PV) rather than following the Fenton reaction. The PV compounds formed would be responsible for P-Tyr increase, Ras induction, and cell death. The results obtained also point to vanadate as a possible chemotherapic in the use of multidrug-resistant tumors.
Capella
Luiz S
LS
Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Gefé
Maria R
MR
Silva
Edson F
EF
Affonso-Mitidieri
Ottilia
O
Lopes
Anibal G
AG
Rumjanek
Vivian M
VM
Capella
Márcia A M
MA
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002374:Catalase / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D004285:Dogs; D018432:Drug Resistance, Multiple / Q000235:genetics; D005978:Glutathione / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000633:toxicity; D007328:Insulin / Q000494:pharmacology; D007668:Kidney; D007700:Kinetics; D008253:Macaca mulatta; D009249:NADP / Q000378:metabolism*; D010641:Phenotype; D015398:Signal Transduction / Q000502:physiology; D013482:Superoxide Dismutase / Q000494:pharmacology; D014638:Vanadates / Q000493:pharmacokinetics / Q000633:toxicity*
D000975:Antioxidants; D007328:Insulin; C069276:peroxovanadate; D014638:Vanadates; D009249:NADP; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase; D005978:Glutathione