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J. Biochem, 1968, Vol. 63, No. 2 156-164
© 1968 Japanese Biochemical Society

research-article

Action Mechanism of Phenothiazine Derivatives on Mitochondrial Respiration*

TAKASHI MATSUBARA** and BUNJI HAGIHARA

From the Department of Biochemistry, Medical School, Osaka University Kita-ku, Osaka

**Present addresses: Shiongi Researxh Laboratory, Shionogi Co., Ltd., Furkushima-ku, Osaka)

The effect of phenothiazine derivatives on the mitochondrial respiratory system was studied. It was found that at low concentrations these compounds stimulated the state 4 respiration, the oligomycin- or tri-n-butyltin chloride-inhibited respiration and also mitochondrial ATPase [EC 3.6.1.3 [EC] ], but at high concentrations they inhibited both state 4 and 3 respiration. Phenothiazine ring structure was necessary for such actions and the substitution at 3- or 10-position of the ring did not alter the qualitative nature of their actions but affected only quantitatively. The sulfoxide compounds gave no effect. A representative phenothiazine derivative, chlorpromazine, inhibited slightly purified cytochrome oxidase [EC 1.9.3.1 [EC] ] even at high concentrations. It inhibited respiration of submitochondrial particles at much higher concentrations than in the case of intact mitochondria. It is concluded that the fundamental action of phenothiazine derivatives is the deformation of membrane structure; uncoupling action is induced when the deformation is slight and inhibition of electron transport is observed when it proceeds extensively.

* A part of this work was presented at the 16th Annual Meeting of the Symposium of Enzyme Chemistry (Tokyo, 1964).


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