MATHEMATICAL-MODEL SUPPORTING THE SUPEROXIDE THEORY OF OXYGEN-TOXICITY

The discovery of superoxide dismutase was followed by a proposal that superoxide anion radical (O2.-) is a major factor in oxygen toxicity. The knowledge of superoxide chemistry, however, led some chemists to c onclude that since O2.- is not very reactive in aqueous solution, the more reactive hydroxyl radical (HO.) was most likely to be the major d amage causing species. Some have defended the superoxide theory by emp hasizing that nonindiscriminate and selective reactivity could provide more toxicity than would high, indiscriminate reactivity. In the pres ent study, network thermodynamic simulation was used to create a situa tion in which O2.- would selectively react with a substrate in a hypot hetical sequence of subreactions supporting biological processes. In t his situation, when the simulation of the chemical reactions was carri ed out using reasonable parametric values found in the literature, the selective reaction of O2.- to one molecule in the sequence caused a 9 5% disruption of the observable process, whereas indiscriminately targ eted HO. attack caused only 0 to 35% inhibition. The major cause of th e weak effect of HO. was found, in this particular model, to be a lack of sufficient availability of HO. due to both its slow generation by the Fenton reaction and a large demand for reactions with inconsequent ial targets. This model supports the superoxide theory of oxygen toxic ity by demonstrating that a simple set of circumstances can quantitati vely lead to the proposed selective superoxide toxicity. The present s tudy also advocates the use of novel network thermodynamic simulation techniques for solving problems concerning biological oxidants and ant ioxidants.