Differential Effect of Phenothiazines on Oxidative Phosphorylation

Abstract

IN a previous communication¹ we directed attention to the biochemical effect of chlorpromazine on electron transport and the coupled phosphorylation. While studying related compounds we have observed that promethazine hydrochloride (10-(2-dimethyl amino-isopropyl) phenothiazine hydrochloride) exerts differential effects on the phosphorylations coupled to the reduction of cytochrome c by β-hydroxybutyrate and by succinate. Table 1 shows that promethazine hydrochloride inhibits the phosphorylation coupled to oxidation of (β-hydroxybutyrate by 30 per cent at 2 × 10⁻⁴ and 4 × 10⁻⁴ M. At the latter concentration, electron transport is powerfully inhibited. The phosphorylation coupled to succinate oxidation is inhibited 50 per cent at 2 × 10⁻⁴ M and essentially abolished at 4 × 10⁻⁴ M, electron transport being little affected. A one-step oxidation was secured by pretreatment of mitochondria, as described by Hunter and Ford². Table 1 also shows that the inhibitor abolishes the phosphorylation coupled to oxidation of ferrocytochrome c.