Lysosomal membrane stabilization and antiestrogen action in specific hormonal target cells.

Abstract

Recent advances in these laboratories in analysis of mechanisms of steroid hormone-induced growth have identified lysosomal function in the triggering of the coupled events leading from selective accumulation of the active agent at the cell periphery, to its rapid, cyclic AMP-dependent traversal of the nuclear envelope, and eventual genie activation of the cellular target. Capture of trophic steroid hormone leads to site-specific labilization of the lysosomal bounding membrane, associated with graded extrusion of characteristic hydrolases and acidic glycolipoprotein matrix. In uterus and preputial gland of the ovariectomized rat, these closely-linked phenomena result in the cascading secondary metabolic responses characteristic of estrogen stimulation. The demonstrated antagonistic effects of glucocorticoids upon estrogen action are paralleled to a striking degree by their capacity, likewise, to accumulate in lysosomal fractions where, in optimal concentrations, they and certain other anti-inflammatory agents produce membrane stabilization. Biochemical and cytomorphologic data have been presented which reveal that the counteractive influence of specific glucocorticoids and estrogens upon relative stability of lysosomal membranes is concordant with the long-recognized antagonistic and competitive interaction of these classes of steroid hormones at membranous interfaces. Conversely, estrogen hyperactivity correlated with exaggerated lytic susceptibility of target-specific lysosomal preparations are observed following exposure to estradiol-17Β <i>in</i><i>vivo</i> in the absence of adrenocortical function. The Β-adrenergic blocking-drug, propranolol, which shares the membrane-stabilizing properties of the glucocorticoids, is also capable of inhibiting estrogen-induced structural labilization of target-specific lyso-somes, as well as certain additional estrogenic functions. DOC and the Α-adrenergic blocking agent, phentolamine, are inert under the same conditions. Thus, it is demonstrated that the counterpoised influence which estrogens and certain membrane-stabilizing agents, respectively, exert upon lysosomo:plasma membrane complex of specific cellular targets is a decisive regulatory factor in the ultimate growth response. The new findings provide a rational integrative approach to numerous unresolved questions on the mechanisms underlying steroid hormone action and its blockade.