THE ACTION OF STEROID HORMONES AT THE CELLULAR LEVEL.

Abstract

Although the complex series of events which occur when a steroid hormone is administered to a human subject or to an intact animal might reflect a series of completely unre!lated activities, they are more likely to be secondary to a few fundamental actions on the celils of the body and it is with this second concept that research in this field has been directed. There are two particular features of steroids which may be important in determining their mode of action. Firstly, they have oxygen substituents at certain typical positions which readily undergo enzymatic oxido-reduction and could, therefore, act as coenzymes or prosthetic groups of enzymes in reactions involving hydrogen transfer. Secondly, steroids are surface active and interact with hydrophobic surfaces producing energy. If the energy were to be absorbed iby a receptor molecule it could modify the structure and hence the biological activity of that molecule. A less well defined change is associated with the ability of steroids to capture electrons; this has recently been measured by Lovelock, Simmonds and Vandenheuvel (1963) who consider that the high electron affinities of adrenocortical hormones, a property unusual among organic compounds, might indicate their ability to participate in or control biological oxidative processes. Laidler and Krupka (1961) compared the association between the steroid and a receptor with the formation of an activated enzymesubstrate Michaelis complex. Entropy and volume changes during activation of enzymes indicate that structural changes occur in the enzyme molecule and such changes might explain the disturbances of membrane permeability in nerve cells associated with structural changes in acetylcholinesterase. A similar mechanism might account for changes induced by steroids in the permeability of cell structures. In this process parts of the receptor molecules having specific binding properties might be masked, unmasked, created or destroyed; as well as causing a redistribution of bound substrates, an alteration in enzymic properties might result. Kimberg and Yielding (1962) studied the inhibition of pyruvate kinase by oestrogens and related compounds and showed by viscometry and electrophoresis structural changes in the enzyme, without a change in molecular weight. Yielding and Tomkins (1962) have reported a steroid-hormone induced loss of activity of crystalline glutamic dehydrogenase due to disaggregation into subunits functioning as alanine dehydrogenase with an uncovering of pyridine-nucleotide binding sites. These authors have been more concerned to show the possibility of such changes rather than to attach great physiological significance to them. Chemical changes in receptor molecules after association could account for the highly theoretical possibility of the formation of active enzymes from inactive precursors. That the receptor itsel-f could be an enzyme cofactor has been considered by Scott and Engel (1961) who obtained physical evidence for the interaction between steroid hormones and purine dinucleotides. This interaction between hormone and a coenzyme associated with a postulated change in the structure of the coenzyme might abolish its hydrogencarrying function, but there was no experimental evidence for this. Apart from oxido-reductive changes, metabolism of the steroid molecule is not thought to be of physiological importance except as a mechanism for steroid inactivation. However, competition for active sites on enzymes as opposed to association with them could be of importance in influencing steroid metabolism itself. The various theories which have been proposed to explain the action of steroid hormones at the cellular level will be considered under the following headings: 1. Effects on membrane permeability and active transport. 2. Effects on hydrogen transfer. 3. Effects on enzyme induction and protein synthesis.