Cytotoxicity from Coupled Redox Cycling of Autoxidizing Xenobiotics and Metals: A Selective Critical Review and Commentary on Work‐in‐Progress

A comprehensive reaction schema for oxidative cytotoxicity is presented, integrating known chemical mechanisms of oxygen radical reactions and observed pathophysiology. The key features of the schema are the coupling of (1) redox cycling of autoxidizable substrates to form the equilibrium pair of superoxide anion (O−2)/and its conjugate acid, perhydroxyl radical (HO2); (2) hydrogen peroxide (H2O2) generation via O−2 dismutation; (3) catalytic redox cycling of metals reducing H2O2 to reactive hydroxyl radicals (OH); (4) direct reaction of OH with target molecules, including critical cell macromolecules and polyunsaturated lipids in membranes; (5) transfer of oxidative potential from initial to distant sites via H2O2 and O−2/HO2 diffusion, lipid free radical chain peroxidations in membranes, and migration of non-radical lipid oxidation products; and (6) cytotoxic damage at those distant sites mediated by reaction of lipid radical species and other lipid oxidation products with critical target molecules (proteins, DNA, etc.). Although there is a broad consensus of agreement within the cognizant research community concerning many aspects of this schema, there exists considerable controversy and/or misconception about several important issues. In this paper critical analyses of four presently controversial points are put forth. (1) The question of metal-dependency of Fenton generation of OH is considered first and data are presented to show that previous observations of apparent H2O2 decomposition by various semiquinone radicals most likely resulted from trace metal contamination. (2) The strong electrophile from H2O2 reduction has sometimes been ascribed to a non-free “crypto-hydroxyl” radical because of failure of traditional scavengers to inhibit its reactions in the expected ways or it has been ascribed to iron-oxy complexes based on similar “atypical” scavenger patterns plus requirements for preformed ferric iron. The behavior of these species in multiphasic, inhomogeneous systems, which is alleged to be inconsistent with that characteristic of OH, is reconciled with the competitive kinetics expected of OH in three situations: (a) compartmentalization at the cellular level (i.e., in vesicles or their membranes) which prevents access of scavengers to the sites of OH generation, (b) site-specificity at the molecular level (OH reaction occurring within a few Angstroms of specific metal-binding sites on macromolecules or in/on membranes), and (c) reactivity of secondary radicals formed by the “scavenging” of OH. (3) The significance of lipids in propagating oxidative damage from the initiation sites of lipid peroxidation to distant sensitive target molecules (proteins and nucleic acids) is discussed, along with the capability of O−2 and H2O2 to serve similar roles in propagating damage from the sites of autoxidation. (4) Finally, some common misinterpretations regarding “scavengers” and inhibitors of oxygen radical reactions from both chemical and metabolic/physiological standpoints are considered in the context of medical implications and applications.