Insu P. Lee

The effects of β-diethylaminoethyl-diphenylpropylacetate (SKF 525-A) on biological membranes—I: SKF 525-A-induced stabilization of human erythrocytes

Abstract β-Diethylaminoethyl-diphenylpropylacetate (SKF 525-A) results in either hemolysis or stabilization of the red cell membrane. These effects are concentration dependent. At higher concentrations of SKF 525-A (10 −3 M), an increase in hemolysis and a decrease in osmotic resistance is noted, whereas a stabilization of the red cell membranes occurs at lower concentrations of 10 −4 –10 −9 M. The hemolysis of the red cell is temperature dependent and hemolysis increases as temperature decreases. The SKF 525-A action appears to be immediate and the effects prolonged. The concentration at which SKF 525-A demonstrates its greatest membrane stabilization corresponded to the first breaking point observed during measurements of surface tension, and thus perhaps indicates the formation of micelles. It can be calculated that one molecule of SKF 525-A occupied 51 A 2 of red cell area. SKF 525-A (10 −4 M) causes a change in the mean cellular volume of red cells over all osmolar concentrations studied. One possible mechanism of action that would account for these findings is that the erythrocyte membrane expands in combination with SKF 525-A in the same way that lipid monolayers interact with various surface-active drugs such as the phenothiazine derivatives. The resulting expansion of the erythrocyte membrane would lead to an increase in the surface area and volume of the red cell and thus decrease osmotic fragility.

Various factors affecting the lethality of cyclohexylamine

Abstract Cyclohexylamine (CHA) is a metabolite of the artificial sweetening agent cyclamate and has been shown to possess sympathomimetic actions like those of tyramine and/or amphetamine. Acute toxicity studies using male albino Swiss Webster mice indicated that CHA lethality is both temperature and aggregation dependent. Toxic doses of CHA produced behavior characterized by general hyperactivity, resembling the signs following amphetamine treatment. CHA appeared to increase body temperature. The lethality after CHA could be correlated with an increase in body temperature at doses lower than 480 mg/kg only. Drug interaction studies demonstrated that chlorpromazine, reserpine, phenoxybenzamine and tolazoline were each capable of protecting mice against CHA-induced lethality. In contrast, pretreatment of mice with SKF 525-A potentiated CHA lethality. This potentiation suggests that CHA is further metabolized to less toxic metabolites in mice. Metabolic studies with carbon-labeled acetate indicated that CHA-treated mice expired more 14 CO 2 than control animals, suggesting an enhanced metabolic rate. Death following doses of CHA greater than 480 mg/kg were not apparently related to the hyperthermia, but probably involved other mechanisms related to the sympathomimetic action of CHA.

Effects of β-diethylaminoethyl-diphenylpropylacetate (SKF 525-A) on biological membranes—II: SKF 525-A-induced effects on the growth and uptake of l-amino acids by Escherichia coli (diploid mutant)☆

Abstract Previous work has indicated that β-diethylaminoethyl-diphenylpropylacetate (SKF 525-A), a well-known inhibitor of microsomal drug-metabolizing enzymes, lowers surface tension and has a biphasic hemolytic effect on the human red blood cell membrane. Present studies further investigate the effect of SKF 525-A on biological membranes and are concerned with the action of SKF 525-A on bacterial cells. A diploid mutant of Escherichia coli which has limited ability to synthesize pyrimidines due to the absence of orotidylate decarboxylase was used for these experiments. SKF 525-A at high concentrations (10 −2 and 10 −3 M) lysed E. coli (diploid mutant) cells either during the exponential or secondary growth phase. However, the rate of cell lysis was greater during the exponential than during the secondary growth phase. The magnitude of cell lysis in both growth phases correlated well with surface activities of SKF 525-A and was linear during the first 30 min. E. coli cells treated with SKF 525-A (10 −5 M) for 4 hr prior to incubation with either uracil or L -isoleucine demonstrated decreased cellular accumulation of these substrates. The degrees of inhibition by SKF 525-A on the cellular uptake of these substrates were similar in spite of the dissimilarity of structures. The phenomena of cell lyses and impaired uptake of metabolic substrates suggest that the effect of SKF 525-A concerns an alteration of the cell wall and/or cell membrane rather than a specific effect on transport mechanisms.