Stimulation by thyroid hormone analogues of red blood cell Ca2+-ATPase activity in vitro. Correlations between hormone structure and biological activity in a human cell system.

Abstract

Human red blood cell membrane Ca2+-ATPase activity is stimulated in vitro by physiological concentrations (10(-10) M) of L-thyroxine (L-T4) and 3,5,3'-triiodo-L-thyronine (L-T3). This human cell system has been utilized to examine a series of iodothyronine and iodotyrosine analogues for structure-activity relationships. Analogue purity was verified by high pressure liquid chromatography. Analogues were studied at a concentration of 10(-10) M and the stimulatory effect of each analogue was compared with that of L-T4 in this system. Essential to Ca2+-ATPase stimulation were occupation of the 3 and 5 phenyl positions by iodide, bromide, or methyl groups, the L-configuration of the alanine side chain, side chain length equal to that of alanine, and a perpendicular (skewed) conformation of the two rings. The 4'-hydroxyl group is not essential to Ca2+-ATPase stimulation in this model system. T3 was 76% as active as T4 in stimulating Ca2+-ATPase activity. The stimulatory effect of 3,5-dimethyl-3'-isopropyl-L-thyronine and 3,5,3',5'-tetrabromo-L-thyronine approximated that of L-T4. Selected tyrosine analogues also stimulated the enzyme. The bioactivities of hormone analogues in this human model of extra-nuclear thyroid hormone action differ in several ways from results obtained previously in other animal model systems in vitro and in vivo.