Reactions of Water-Soluble Alkylperoxyl Radicals and Superoxide with DNA, Lipoproteins and Phospholipid Vesicles:The Role Played by Electrostatic Forces

Abstract

The role of electrostatic forces in free radical biology is very important but it is all too often overlooked. The radicals discussed in this review include positively-charged, negatively-charged and neutral water-soluble alkylperoxyls and superoxide. Important scientific insights have been gained by generating these radicals in known quantities by the thermal decomposition of simple, "clean", chemical precursors in the presence of potential bio-targets. For example, the abilities of these radicals to damage double-stranded DNA, a polyanion, are dictated by Coulombic forces with only the positively-charged peroxyls being capable of directly producing single-strand breaks. The Coulombic control of the reactions and reaction rates of water-soluble peroxyl radicals which are so evident with DNA do not manifest themselves with all electrostatically charged bio-targets, e.g., low density lipoprotein (LDL), probably because the charge on the surface of the LDL is not uniformly distributed.

Cytotoxicity and Cytoprotective Activity of Naphthalenediols in Rat Cortical Neurons

“…Cytoprotection against AAPH. It is known from the work of Ingold and co-workers ( − ) that AAPH decomposes with a unimolecular rate constant of 2 × 10 -6 s -1 into two positively charged carbon radicals. These rapidly add oxygen and may, therefore, be represented as + AOO • .…”

“…In contrast, little work has been done on the systematic design of antioxidants targeted toward reducing age-related neurodegenerative disease, but such designer antioxidants are attracting increasing attention now that the principles behind antioxidant design are relatively well understood (6)(7)(8)(9)(10). In a previous work (11) using adherent PC-12 adrenal cells, we subjected the cells to oxidative stress in the form of AAPH (2,2′-azobis (2amidinopropane) hydrochloride), which generates a continuous flux of alkylperoxyl radicals (12)(13)(14)(15). Cytotoxicity studies showed that 1,2-naphthalenediol (1,2-ND) and 1,4-ND were quite toxic and were thus ruled out as potentially useful antioxidants.…”

Oxidative Modification of Guanine Bases Initiated by Oxyl Radicals Derived from Photolysis of Azo Compounds

“…The water-soluble 2,2′-azobis(2-amidinopropane) dihydrochloride (known as ABAP28 or AAPH29) has been extensively used to initiate lipid peroxidation,30-32 to explore effects of oxidative stress on cultured cells33-36 and signaling responses associated with inflammation and aging 37. Ingold and co-workers have shown that the thermal decomposition of AAPH in oxygenated neutral solutions generate both strand breaks and base modifications of supercoiled DNA 21-23. In turn, neutral and negatively-charged peroxyl radicals derived from the decomposition of 2-methyl- N -(2-hydroxyethyl)propionamide and 2,2′-azobis[2-methyl- N -(2-hydroxyethyl)propionamide], respectively, were at least two orders of magnitude less effective in generating DNA strand scission.…”

“…Persistent inflammation, which is a fundamental physiological defensive reaction against a variety of viral and microbial infections, environmental pollutants, tobacco smoke, and other exogenous factors, becomes harmful if transformed to a chronic form. − Oxidative stress associated with chronic inflammation is characterized by the overproduction of reactive oxygen species (ROS) that can cause oxidative damage to diverse biomolecules. − These ROS induce peroxidation of membrane lipids and the accumulation of lipid hydroperoxides that break down into reactive intermediates such as electrophilic aldehydes, epoxides, − and alkylperoxyl and alkoxyl free radicals. − The chemistry and genotoxic effects of covalent DNA adducts generated by electrophilic aldehydes and epoxides derived from lipid peroxidation have been studied extensively. − Although oxidative damage to DNA exposed to lipid oxyl radicals has been documented, − the detailed mechanisms remain poorly understood due to the complexities associated with the interconversion, fragmentation, and structural characterization of lipid peroxyl and oxyl radicals.…”

Oxidation of 8-Oxo-7,8-dihydro-2′-deoxyguanosine by Oxyl Radicals Produced by Photolysis of Azo Compounds

“…The thermal and photochemical decomposition of azo compounds is a classical approach for the controlled generation of alkylperoxyl radicals . The water-soluble 2,2′-azobis(2-amidinopropane) dihydrochloride [known as ABAP or AAPH ] has been extensively used to initiate lipid peroxidation − , to explore the effects of oxidative stress on cultured cells − , oxidation of DNA − , and signaling responses associated with inflammation and aging . Our own laser flash photolysis experiments have shown that the photolysis of AAPH generates a whole spectrum of free radicals including 2-amidinoprop-2-peroxyl (ROO • ), 2-amidinoprop-2-oxyl (RO • ), and superoxide (O 2 •− ) radicals .…”