THE EFFECT OF ATABRINE AND QUININE ON ISOLATED RESPIRATORY ENZYMES

Abstract

Oxygen consumption and utilization of glucose appear to play an important role in cultivation and survival of malaria parasites (l-4).Antimalarial drugs effectively inhibit respiration of the parasite (5, 6) and comparable inhibition of the respiration of mammalian tissue by atabrine (7) has been reported by Wright and Sabine.'It is conceivable that the inhibition of parasite respiration observed in vitro is indicative of a similar process taking place in the body when the drug is therapeutically effective.Therefore it seemed desirable to investigate the action of antimalarials on the isolated components of the respiratory enzyme system.Knowledge of the effects of these important drugs on enzymes of known structure may offer a better understanding of the mechanisms of therapeutic activity and toxicity.In Fig. 1 the components of the respiratory system are arranged in the order in which they react with each other, with molecular oxygen, and with the substrate.By selecting proper concentrations conditions can be so adjusted that any reaction in this scheme becomes the rate-determining factor.Specific tests were developed, by use of spectrophotometric and manometric methods, permitting precise investigation of the action of the drug on each component.Detailed descriptions of the tests are given to facilitate studies on the effect of therapeutic agents on various components of the respiratory system.Additional information may be gained by considering intermediate steps rather than by studying over-all reactions.Inhibition of Cytochrome Oxidase-The enzyme was prepared according to the new procedure (8).Enzymatic activity and inhibition were measured in Warburg manometers after incubation at 25" in O.Q5 M phosphate buffer of pH 7.1.Incubation of the enzyme with atabrine for 15 minutes or for 8 hours produced the same inhibition.The effect of atabrine and of quinine on cytochrome oxidase is shown in Table I.Under these conditions the oxygen consumption is proportional to the