Mechanism of metal-independent decomposition of organic hydroperoxides and formation of alkoxyl radicals by halogenated quinones

Abstract

The metal-independent decomposition of organic hydroperoxides and the formation of organic alkoxyl radicals in the absence or presence of halogenated quinones were studied with electron spin resonance (ESR) and the spin-trapping agent 5,5-dimethyl-1-pyrroline N-oxide (DMPO). We found that 2,5-dichloro-1,4-benzoquinone (DCBQ) markedly enhanced the decomposition of tert-butylhydroperoxide (t-BuOOH), leading to the formation of the DMPO adducts with t-butoxyl radicals (t-BuO • ) and methyl radicals ( • CH3). The formation of DMPO/t-BuO • and DMPO/ • CH3 was dosedependent with respect to both DCBQ and t-BuOOH and was not affected by iron-or copper-specific metal chelators. Comparison of the data obtained with DCBQ and t-BuOOH with those obtained in a parallel study with ferrous iron and t-BuOOH strongly suggested that t-BuO • was produced by DCBQ and t-BuOOH through a metal-independent mechanism. Other halogenated quinones were also found to enhance the decomposition of t-BuOOH and other organic hydroperoxides such as cumene hydroperoxide, leading to the formation of the respective organic alkoxyl radicals in a metal-independent manner. Based on these data, we propose a mechanism for DCBQ-mediated t-BuOOH decomposition and formation of t-BuO • : a nucleophilic attack of t-BuOOH on DCBQ, forming a chloro-t-butylperoxyl-1,4-benzoquinone intermediate, which decomposes homolytically to produce t-BuO • . This represents a mechanism of organic alkoxyl radical formation not requiring the involvement of redox-active transition metal ions.electron spin resonance spin-trapping ͉ 2,5-dichloro-1,4-benzoquinone ͉ 2,5-dichlorosemiquinone anion radical ͉ reactive intermediate ͉ metal chelators O rganic hydroperoxides (ROOH) can be formed both nonenzymatically by reaction of free radicals with polyunsaturated fatty acids and enzymatically by lipoxygenase-or cyclooxygenasecatalyzed oxidation of linoleic acid and arachidonic acid (1, 2). It has been shown that organic hydroperoxides can undergo transition metal ion-catalyzed decomposition to alkoxyl radicals (Reaction 1), which may initiate de novo lipid peroxidation or further decompose to ␣,␤-unsaturated aldehydes that can react with and damage DNA and other biological macromolecules (1, 2).where Me represents a transition metal, such as iron or copper. Using the salicylate hydroxylation assay and electron spin resonance (ESR) spin-trapping methods, we reported previously that HO • can be produced from H 2 O 2 by halogenated quinones independent of transition metal ions (3, 4). However, it is not clear whether halogenated quinones react in a similar fashion with organic hydroperoxides to produce alkoxyl radicals independent of transition metal ions.Therefore, in the present study we addressed the following questions. (i) Can halogenated quinones enhance the decomposition of organic hydroperoxides to produce alkoxyl radicals? (ii) if so, is the production of alkoxyl radicals dependent or independent of transition metal ions? (iii) And what is the underlying molecular mechanism? To c...

The first purification and unequivocal characterization of the radical form of the carbon-centered quinone ketoxy radical adduct

“…4 We have recently shown that halogenated quinones could enhance the decomposition of hydroperoxides and formation of alkoxyl/hydroxyl radicals independent of transition metal ions. [5][6][7][8] A new carbon-centered quinone ketoxy radical ( CBQ-OH, MW: 157) adduct with the spin-trapping agent DMPO (5,5-dimethyl-1-pyrroline N-oxide) (simply referred to here as DMPO-157) was observed during the reaction between 2,5-dichloro-1,4-benzoquinone (DCBQ) and t-butylhydroperoxide (t-BuOOH). 7 However, although we can observe the ESR signal for DMPO-157, we cannot directly detect its nitroxide radical form, but only its corresponding more stable non-radical nitrone form, by mass spectrometry (MS).…”

“…[5][6][7][8] This work was supported by NSFC Grants (21237005, 20925724, 21077058 and 21107139) and NIH Grants (ES11497, RR01008 and ES00210) (B.Z.). The authors also acknowledge the technical help provided by Dr H. T. Zhao.…”

Characterization of TCHQ-induced genotoxicity and mutagenesis using the pSP189 shuttle vector in mammalian cells

“…And during the autoxidation of TCHQ to TCBQ, the producing O 2 •− radical could be changed into H 2 O 2 , and producing OH . radicals from the reaction of H 2 O 2 and TCBQ could do damage to DNAs as demonstrated by Zhu et al [8,[22][23][24]. Therefore, we also examined the induction of oxidative DNA damage by H 2 O 2 and TCBQ, a metabolite of the TCHQ autoxidation reaction.…”

“…However, when DNA was administered along with H 2 O 2 and TCBQ, differences in the DNA strand breakage became significant when compared with the control. Mechanisms by which hydroxyl radicals are produced from TCBQ/H 2 O 2 have been verified as a metal-independent molecular mechanism [22,23]. During this reaction, TCBQ not TCSQ radical is essential to produce OH .…”

Molecular Mechanism of Metal-Independent Decomposition of Organic Hydroperoxides by Halogenated Quinoid Carcinogens and the Potential Biological Implications

“…22 It is worth noting that a small radical signal was also detected in both DCBQ and 2,6-dichloro-1,4-benzoquinone (2,6-DCBQ) systems but could not be observed in Fe and other XQ systems (for further identification of this radical adduct, see section 3 below). In contrast, incubation of either compound alone did not lead to t-BuO • or • CH 3 generation (Figure 3).…”