New Facets of the Biochemistry of Steroid Hormone Actio& H. G. WILLIAMS-ASHMAN (The James Buchanan Brady Urologicat In.@titute, The John.@ Hopkins Ho.@pi1ul, and 7'he Department of I'harmacology and Experimental Therapeu1ic.@, The JOhnS Hopkins (Tniver.sity School of .tfedicine, Baltiniore, Maryland 21205) SUMMAR ‘@: Some aspects of i-ecent experimental appi-oaches to the molecular l)aS)s of steroid hormone action are reviewed. Among the topics considered are: (1) the bearing of structure-activity relationships, and of pathways for the metabolism of steroid hor mones, on the I)roblem of the nature of the I)rimary cellular receptors for these hor mones; (2) coenzyme-like actions of sex hormones in isolated enzyme systems; (3) steroid hormones as allosteric effectors ; (4) steroid hormones u.s regulators of gene cx pres.sion and of intermediate reactions involved in nucleic acid and protein synthesis. There has beeii a prodigious increase iii the volume and bioassay systems are just. as striking as their specificities. variety of recent experiment at attacks on the problem of Indeed, the very concept of “targetorgans― for certain the molecular basis of stei-oid hormone action. This steroids is of doubtful significance. There are abundant. paper will not attempt aiiy coniprehetisive coverage of this examples of a single steroid inducing dissimilar or even per@)1exingfield, but is rather restricted to consideration of completely opposing effects on various tissues in the same a few arbitrarily selected researches that have excited much animal. The variations in the response of many neo effort and controversy and that attest to the truth that. i)lasrns to different steroids (or combinations thereof) am-c the “difficultyiii most scientific work lies in framing the particularly baffling, especially in those all too common (luestiolls rather than iii finding the aiiswers― (18). A cases where the tumors may eventually lose their hormone great deal of interesting @voi-kon interactions of steroid dependence (20, 95, 96, 101). It is obvious that changes hormones with biologic membranes (86, 262, 268, 277) rep iii the biologic effects of steroids resulting from alterations resents but one of the many inmpoi-t.ant areas of contem in subst.ituent groups or molecular geonietry may reflect [email protected]@Yinvestigation which are largely omitted from the not only differences in the reactivity of these substances Pi@eSe11t discussion. toward their primary hormonal receptors, but also the operation of other factors, such as the nature and extent of STRUCTURE-ACTIVITY RELATIONSHI PS, the metabolic transformations of the hormones (in their STEROID METABOLISM, AND THE target tissues or elsewhere) ; the relative distribution of the RECEPTOR PI{OBLEM steroids and their metabolites among various organs, cells, A vast heap of information is now extant concerning and organdIes; and so forth. For it is well established relat ions of the primary chemical structure of steroids and that exogenous steroids can be converted in vivo into sub related substances to their activities in various bioassay stances with enhanced or altered types (cf. Refs. 13, 26, systemns (7, 25, 26, 46, 193, 203). Appelations such as 114) of biologic activity, in addition to being “inactivated― ‘‘androgen,' ‘ ‘‘estrogen , ‘‘‘‘gestageii, ‘‘‘‘mineralocorticoid,― (13, 26, 236, 239). Indeed, we cannot even be sure at and “glucocorticoid― have, of course, a purely operational present as to the nature of the “activeforms―of steroid inemuming, and it is practically impossible to overestimate hormones in susceptible cells, although there are yet no the (.ofliplexit.y of the biologic respotises to which they coiiipelling reasons to believe that testosterone, estradiol refer. This is strikingly illustiated in the realm of female 17@, and progesterone do imot combine as such with the reproductive physiology by the studies of Huggins and receptors responsible for their sex hormonal actions.2 .Jensen (97—100) on the so-called impeded estrogens amid on For these amidother reasons, reflections on the electronic the repertoire of vaginal responses to different steroids, as structure and molecular geometry of steroids and synthetic well as by the dependence of estrogenic effects on local estrogens have contributed little solid insight into the na V(iSUS systemic adniinistrat ion of aromatic substances ture of the hormonal receptors. There may be limitations which led Emmens et a!. (52) to enunciate the concepts of to the heuristic value of rather general concepts such that “@)roestrogen―and“trueestrogen.― So often, the over the attachment of steroids t.o their receptors occurs at mul @ im@l)s the biologic activities of various steroids in many tiple points (203) ; that electrostatic and London dispersion @ Original work from the authors laboratory was supported by 2 Jensen aIRI Jacobsoti's (ill) hypothesis that estroiie must Grant HJ)-0l266 from the National Institute of Child Health and he converted into estradiol-17fl before it. can exert uterotropic Hurn:tir l)evelopment and (ra,il CA-tE545 from the National action has l)eeli criticized on experimental grounds by Stone arid (‘nilcer Institute. Martin (230). 1096 Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1965 American Association for Cancer Research. WILLIAMs-AsHMAN—Steroid Hormone Action 1097 forces, hydrogen, and hydrophobic bonds may all be in (224, 225, 232, 233) have obtained evidence—albeit some volved in their emigagement with the receptors (26, 203); what tenuous (34)—that many of the actions of estrogens and that when the latter occurs, restrictions may be im oil the uterus may be due to liberation of histamine and posed on the translational degrees of freedom of the ste perhaps serotonin, possibly from mast cells. Naturally, roids (26). This is not to detract from the utility of any comprehensive account of hormone action must spec certain purely empirical geiieralizations—such as Fried (56, ify the chronology of the induced biochemical events. But 57) proposed with respect to the activities of halogenated here one must be on guard against the pitfalls of post hoc, steroids—in sem-ving as fruitful guides for synthesis of ergo propter hoc fallacies. highly active novel compounds. Scrutiny of 2-dimen The idea that the cellular receptoms for most drugs amid sional structural formulae may certainly be misleading in hormones must be proteins, rather than any other class of consideration of structure-activity relationships, amid the mnacromolecule, is firmly entrenched in contemporary bio importance of the exact. conformations that the steroids logic thought. Because they are coml)rised of so niaiiy can assume in solution has been emphasized repeatedly more types of building blocks thaim are either polysacelia (26, 203, 236). Especially iii the field of the aronmt.ic rides or polynucleotides, the proteins are clearly capable of estrogens—where the geometrical requirements are less a much greater variety of localized and sterospecific dOffi stringent thami with the androgens, gestagens, and corti plememitary imiteractions with sniall molecules, and also of coids—perhaps not enough att.entioim has been paid to their subtle modifications of their tertiary structures. It is mr-electronic emiergy levels, now that these are becoming only natural that, of the host of proteins present in cells, more tractable to coml)utatioli (150). Here we may men various emizymes and structural membrane proteins should tion some recent l)ointers (40, 102) to analogies between have been considered as candidates for hormone receptor the molecular geometries of hormuonally active sten-oids (as functions. The overwhelming emphasis on enzynies iii well as of some carcinogenic aromatic hydrocarbons) aiid their cytoarchitectural context as the all-importanit utmits the base pairs of DNA. determining cell structure and function, so ably elaborated Today it remains an entirely open question as to whethem on by Mueller (162) at a comparable symposium 7 yeai@s t he effects of any one steroid hormone on any particular ago, is very characteristic of the Zeitgeist. But the ye cell are set in motion via a number of different types of markable progress imithe biochenmistry of protein synthesis l)rimary biochemical interaction (perhaps at varyimig intra and gene expressiomi over the intervening years has now cellular locations), or rather as a result of a single basic pointed to various types of 1)olymmucleotideas the primary physicochenucal event which triggers off all subsequent targets for some physiologically active trace substances. physiologic responses. That a given steroid affects all This seems to be the case, for example, with respect to the susceptible normal and mieoplastic cells by the same basic action of certain alkylating agents (48, 87) and of ant ibi niechamiism is also purely a matter of conjecture. Ingle's otics such as actimiomyciri D (84, 188, 190). And it. is well (106) incisive experiments pointing to the “permissive― established that sonic purinie and j)yrimidine analogs nitty ttct iOU of steroids show how careful one must be iii talking inifluemicebiologic i@roces@esasa result of being incorporat ed about the “regulatory―action of certain hormones. As into “fraudulent―polymiucleotide structures (48, 87, 104). Bush (26) neatly puts it : “Everyresponse that was cx The melancholy failure of so niany attempts to “explain― mtmined which had previously been supposed to be subject. homiuone action imiternis of priniary classical chemnical in to the regulatory action of the glucocorticoids of the adrenal teractions with macromolecules in solution has eveim led cortex (cortisol amidcorticost.erone) was shown by this type some authors to imagine that. hoimones may act accordimig of experiment to depend upon the presence of this type of to entirely different pm'imiciples,which could only be cx steroid but to be under the regulation of some other sys pressed in the language of the quantum theory of solids.