| Autor: |
Kurella EG; Department of Environmental and Occupational Health, University of Pittsburgh, PA 15238, USA., Osipov AN, Goldman R, Boldyrev AA, Kagan VE |
| Jazyk: |
angličtina |
| Zdroj: |
Biochimica et biophysica acta [Biochim Biophys Acta] 1995 Nov 21; Vol. 1232 (1-2), pp. 52-8. |
| DOI: |
10.1016/0005-2728(95)00115-0 |
| Abstrakt: |
In the present work, we studied the effects of phenoxyl radicals, generated by tyrosinase-catalyzed oxidation of a phenolic antitumor drug, Etoposide (VP-16), on a purified dog kidney Na+/K(+)-ATPase by characterizing interactions of VP-16 phenoxyl radicals with the enzyme's SH-groups by ESR and correlating the loss of the enzymatic activity with the oxidation of its SH-groups, and oxidation of VP-16. VP-16/tyrosinase caused inhibition of Na+/K(+)-ATPase which was dependent on the incubation time and concentration of tyrosinase. The inhibition of Na+/K(+)-ATPase was accompanied by a decrease of DTNB (5,5'-dithiobis-(2-nitrobenzoic acid)-titratable SH-groups. In the presence of Na+/K(+)-ATPase, a typical ESR signal of the VP-16 phenoxyl radical could be observed only following a lag period the duration of which was proportional to the concentration of the Na+/K(+)-ATPase added. Our HPLC measurements demonstrated that Na+/K(+)-ATPase protected VP-16 against tyrosinase-catalyzed oxidation. Combined these results suggest that redox-cycling of VP-16/VP-16 phenoxyl radical by SH-groups of Na+/K(+)-ATPase occurred. Ascorbate which is known to reduce the VP-16 phenoxyl radicals, protected the enzyme against inactivation, prevented oxidation of the enzyme's SH-groups. Reduction of VP-16 phenoxyl radicals by ascorbate was directly observed by the semidehydroascorbyl radical signal in the ESR spectra. VP-16 phenoxyl radical-induced oxidation of sulfhydryls and inhibition of the Na+/K(+)-ATPase may be responsible for at least some of its clinical side effects (e.g., cardiotoxicity) which can be prevented by ascorbate. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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