ANTIOXIDANT PARADOXES OF PHENOLIC-COMPOUNDS - PEROXYL RADICAL SCAVENGER AND LIPID ANTIOXIDANT, ETOPOSIDE (VP-16), INHIBITS SARCOPLASMIC-RETICULUM CA2+-ATPASE VIA THIOL OXIDATION BY ITS PHENOXYL RADICAL

被引：41

作者：

RITOV, VB ^{[1
]}

GOLDMAN, R ^{[1
]}

STOYANOVSKY, DA ^{[1
]}

MENSHIKOVA, EV ^{[1
]}

KAGAN, VE ^{[1
]}

机构：

[1] PITTSBURGH CANC INST, PITTSBURGH, PA 15238 USA

来源：

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS | 1995年 / 321卷 / 01期

关键词：

CA2+-ATPASE; PHENOXYL RADICAL; PEROXYL RADICAL; ANTIOXIDANT; VP-16; THIOLS; SARCOPLASMIC RETICULUM; TYROSINASE; ASCORBATE; AZO-INITIATORS;

D O I：

10.1006/abbi.1995.1379

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The effectiveness of a phenolic antioxidant as a radical scavenger is determined by its reactivity toward peroxyl radicals and also by the reactivity of the antioxidant phenoxyl radical toward oxidation substrate, If the phenoxyl radical efficiently interacts with vitally important biomolecules, this interaction may result in oxidative damage rather than antioxidant protection, In the present work, we studied effects of phenoxyl radicals generated from a phenolic antitumor drug, Etoposide (VP-16), on oxidation of thiols and activity of Ca2+-ATPase in sarcoplasmic reticulum (SR) membranes from skeletal muscles, We found that VP-16 is an effective scavenger of peroxyl radicals as judged by its ability to inhibit a water-soluble ate-initiator, 2,2'-azobis(2-amidinopropane)dihydrochloride (AAPH)-induced (i) chemiluminescence (oxidation) of luminol, (ii) fluorescence decay (oxidation) of cis-parinaric acid incorporated in SR membranes, and (iii) peroxidation of SR membrane lipids, VP-16 did not prevent AAPH-induced oxidation of sulfhydryl groups and inhibition of Ca2+-ATPase in SR membranes, Electron spin resonance measurements showed that AAPH-induced VP-16 phenoxyl radicals were reduced by interaction with SR thiols, By using tyrosinase to generate VP-16 phenoxyl radicals as the only source of free radicals in the model system, we found that inhibition of Ca2+- ATPase was accompanied by oxidation of about 5 mol of Ca2+-ATPase SH groups per 1 mol of oxidized VP-16, Secondary products of VP-16 oxidation (including VP-16 o-quinone) were not efficient in inhibiting SR Ca2+; ATPase, Reduction of VP-16 phenoxyl radicals by ascorbate protected against AAPH- and tyrosinase-induced thiol oxidation and Ca2+ ATPase inhibition, The results suggest that efficient phenolic scavengers of peroxyl radicals such as VP-16-which are commonly considered as potent antioxidants-may themselves produce oxidative stress due to secondary reactions of their phenoxyl radicals with thiols, (C) 1995 Academic Press, Inc.

引用

页码：140 / 152

页数：13

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