Chemical Competition in Target Radical Reactions: Numerical Simulation of the Theory and Comparison with Measured Oxygen Effect on DNA Damage in Cells

Summary

An intracellular radiation-chemical reaction scheme is tested in which solute and solvent radicals R· react with non-target molecules Sa (scavengers) or with target molecules (presumed to be DNA) to produce target radicals T·, which may also be produced by direct ionization of DNA. The rate of target radical decomposition to become ‘uncommitted damage’ that the cell may repair is affected by the concentration of oxygen (O₂), thiols (S) and electronaffinic sensitizers (F), which compete with one another to form, respectively, target products TO₂, TS and TF. This uncommitted damage is then subject to biochemical modification, including molecular repair, by the cell. The rate equations for this competing reaction scheme were written and programmed for computer simulations of changes in oxygen, thiol and electronaffinic sensitizer concentrations. A reaction scheme that also includes some non-radical target damage was also simulated. Simulations were made using available experimental data concerning intranuclear concentrations and reaction rate constants, respectively, k_o, k_s and k₁ for the reactions T· + O₂→TO₂, T· + S→TS and T· + F→TF, which produce uncommitted chemical damage. Experimental data on strand-break induction in glutathione-proficient and glutathione-deficient cells, in cells treated with thiol active agents, and in cells treated with hypoxic sensitizers, along with the computer simulations, generally agree that thiol molecules can react with target radicals to reverse T· in competition with O₂ and/or electronaffinic sensitizers.

Forward reaction rate constants k_o, k_s (dithiothreitol), k_s (glutathione) and k₁ (misonidazole) in the approximate ratio 10 : 0·3 : 0·02 : 0·4 satisfied the above reaction scheme, and approximately 5 per cent non-radical target molecule damage could be included with satisfactory agreement with experimental data.

• thiols
• oxygen enhancement ration (OER)
• single-strand DNA breaks
• radiation chemical models
• glutathione