Metabolism induced binding of 14C-misonidazole to hypoxic cells: kinetic dependence on oxygen concentration and misonidazole concentration.

Under conditions of extreme hypoxia, metabolic products of the metabolism of misonidazole bind to cellular molecules at a rate which is linear with time and proportional to the square root of misonidazole concentration. Very small amounts of oxygen reduce the overall rate of binding and cause a change in the dependence on misonidazole concentration from square root (half order) to linear (first order). Because of the known electron affinity of misonidazole, a model is presented whereby the nitro-group is reduced to a radical in a first order reaction. This radical binds to cellular molecules in a slow first order reaction and either disproportionates or dimerizes in a fast second order reaction. Based on the overall effect of oxygen on the kinetics of the rate of binding, the radical is tentatively assumed to be the 3 electron reduction product.