Reactivity of various phenothiazine derivatives with oxygen and oxygen radicals

7,8-Dihydroxychlorpromazine, 7,8-dihydroxyprochlorperazine and 7,8-dihydroxyperphenazine all reacted with O₂ to make hydrogen peroxide (H₂O₂). The rate of reaction between the ortho-dihydroxyphenothiazines and O₂ was increased by superoxide dismutase, an enzyme which catalyzes the dismutation of the superoxide radical (O₂^?) to H₂O₂ and O₂. This indicated the formation of O₂^? during the autoxidation of the ortho-dihydroxyphenothiazines. Several phenothiazines lacking the ortho-dihydroxy groups did not consume O₂ at a detectable rate (did not generate H₂O₂). All ortho-dihydroxyphenothiazines tested also reacted with O₂ in the presence of methional to form ethylene. Ethylene formation was inhibited by catalase and hydroxyl radical (·OH) trapping agents, such as sodium benzoate; this indicated ·OH formation from the ortho-dihydroxyphenothiazines. In addition, several nonhydroxylated phenothiazines and monohydroxylated phenothiazines inhibited ethylene generation from 6-aminodopamine, which also generates ·OH. This inhibition was probably mediated by a reaction between the phenothiazine and ·OH. All of the above reactions (generation of H₂O₂, O₂^? or ·OH or reaction with ·OH) may be responsible for some of the beneficial and/or adverse effects of administered phenothiazines.