Toxic drug effects associated with oxygen metabolism: redox cycling and lipid peroxidation

Abstract

Various endogenous and exogenous compounds exert cytotoxic effects via oxygen reduction. In general, these are reduced by intracellular enzymes (reductases of various kinds) in one-electron transfer reactions, before they in turn reduce O2 to O2, the superoxide anion radical. Thus, a cycle is formed of O2 uptake at the expense of cellular reducing equivalents, notably NADPH, generating further active oxygen species (figs 1,2). Structures capable of 'redox cycling' include catechols and other quinone compounds, iron chelates, and aromatic nitro compounds. Several anticancer agents, and also some mutagens, operate on this principle, and their toxic effects may be explained by redox cycling. The particular importance of hypoxic conditions for deleterious O2 effects is given by the concomitant flux through reductive as well as oxidative pathways. Toxic effects include membrane damage resulting from peroxidative reactions of polyunsaturated fatty acids (lipid peroxidation), as well as the attack of reactive oxygen species on proteins (enzymes) and nucleic acids; thus O2 metabolism is linked to carcinogenicity and mutagenicity. Lipid peroxidation is also induced by various halogenated compounds such as carbon tetrachloride. Again, hypoxic conditions are particularly critical because, on the one hand, metabolic activation leading to the free radical is enhanced and, on the other hand, oxygen required for the maintenance of lipid peroxidation is still available. - Powerful antioxidant systems of the cell maintain low steady state concentrations of oxygen metabolites, and toxic effects may, in part, also be explained by the constant drain of reducing equivalents resulting from redox cycling.