The intensity of vanadium(V)-induced cytotoxicity and morphological transformation in BALB/3T3 cells is dependent on glutathione-mediated bioreduction to vanadium(IV).
Cytotoxicity and morphological transformation has been studied in BALB/3T3 Cl A31-1-1 mouse embryo cells for ammonium vanadate [vanadium(V)] and vanadyl sulphate [vanadium(IV)] alone or in combination with diethylmaleate (DEM), a cellular glutathione (GSH)-depleting agent. Cells exposed for 24 h to 10(-5) M vanadium(V) alone or in combination with 3 x 10(-6) M DEM showed the characteristic hyperfine EPR signal of vanadium(IV), which was more obvious in the case of exposure to vanadium(V) alone. This suggests that the amount of vanadium(V) reduced to vanadium(IV) decreased in GSH-depleted cells. While vanadium(IV) at concentrations of 3 x 10(-6) M and 10(-5) M was not transforming in the cells, vanadium(V) showed neoplastic transforming activity (P < 0.025 and P < 0.001 for the two doses, respectively) in comparison to controls (vanadium unexposed cells). Cytotoxicity and morphological transformation in cells exposed to vanadium(V) in combination with 3 x 10(-6) M DEM were significantly more intensive (P < 0.005 and P < 0.01 for the two doses of vanadate tested) compared to the corresponding values observed in cells exposed to vanadium(V) alone. This suggests that the final transforming activity response is dependent on the intracellular GSH-mediated mechanism of reduction of vanadium(V) to vanadium(IV): (i) the extent to which vanadium(V) should be bioreduced to less toxic vanadium(IV) via intracellular GSH is a key point in determining the intensity of the observed neoplastic action; (ii) the carcinogenic potential of vanadium(V) should be strictly dependent on its intracellular persistence which could lead to changes in normal metabolic patterns of vanadium(V) in the oxidized form due to lack of GSH-mediated reduction.
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Commission of the European Communities, Environment Institute, Joint Research Centre-Ispra Site, Varese, Italy.
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Fischbach
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D016475:3T3 Cells; D000818:Animals; D001711:Biotransformation; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004578:Electron Spin Resonance Spectroscopy; D005978:Glutathione / Q000378:metabolism*; D008298:Maleates / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D010084:Oxidation-Reduction; D017968:Vanadium Compounds / Q000378:metabolism / Q000633:toxicity*
D008298:Maleates; D017968:Vanadium Compounds; C034028:vanadyl sulfate; C014476:diethyl maleate; D005978:Glutathione