Interactions of the antitumor drug, etoposide, with reduced thiols in vitro and in vivo.
The interaction of activated etoposide, 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidene-beta-D-glucopyra noside) (VP-16), with thiols has been studied both in vitro and in vivo in mice. We have found that both glutathione (GSH) and cysteine rapidly reduce the VP-16 free radical, which results in the regeneration of the parent drug and the oxidation of the thiol. Using spin-trapping and electron spin resonance (ESR) techniques, we have shown that this one-electron/hydrogen donation by thiols forms thiyl radicals (RS.) which are intermediates for the formation of the oxidized thiols. The administration of VP-16 in vivo to mice decreased the total thiol levels in liver and concomitantly increased the formation of oxidized thiols. Furthermore, VP-16 stimulated glutathione reductase in liver. While administration of VP-16 also increased the total thiol pools in kidney, in contrast, no significant effects were observed on lung and heart thiol pools.
D000818:Animals; D003497:Cyclic N-Oxides; D003545:Cysteine / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D005047:Etoposide / Q000378:metabolism*; D005609:Free Radicals; D005978:Glutathione / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction; D013438:Sulfhydryl Compounds / Q000378:metabolism*
D003497:Cyclic N-Oxides; D005609:Free Radicals; D013438:Sulfhydryl Compounds; D005047:Etoposide; C017245:5,5-dimethyl-1-pyrroline-1-oxide; D005978:Glutathione; D003545:Cysteine