Lecture Notes 19 Farmakologi Anti Inflamasi Steroid dan OAINS
Mechanism of Steroid Hormone Activity Investigated
1
Λ. L. Wilds, University of Wisconsin; U. V. Sohnssen, Warner institute; and Louis Fieser, Flctrvai^I University, at meeting Tf. W. Barrett, Colorado State College, and E. E. Hays, Armour Laboratories, trade notes Mechanism of Steroid Hormone Activity Investigated A STAFF REPORT XTL GREAT mass of new empirical data was presented to about 200 organic and bio- chemists and physiologists in the field of steroid hormones at a symposium sponsored by the University of Wisconsin at Madison on Sept. 6 through 8. Although much time was devoted to discussion of the pre- cise mechanism of steroid hormone activity and of the correlation of physical arid structural characteristics with physiologi- cal activity, there were few glimmers of light cast upon this exceedingly complex subject. However, in one of the prelimi- nary talks Louis F. Fieser of Harvard Uni- versity reviewed the promising positive advancements which have been made in the last few years in determining the physical structure of the steroid com- pounds. Although some of the structures advanced are still being questioned, the solution of the structural chemical part of the problem seems imminent. He also quoted the recent adaptation of the new techniques of physical chemistry to bio- logical problems. Some investigations with radioactive tracers have already achieved results in the study of endo- crinological activity, particularly in the metabolism of cholesterol. Absorption spectroscopy has proved a particular^' effective tool because the significant con- jugated polyene and ketone configurations produce adsorption in the ultraviolet while hydroxyl groups and isolated car- bonyl groups affect the near infrared ab- sorption. The determination of optical activity has also proved a rich source of informa- tion on structure and configuration and has been directly responsible for the struc- tural determination of a number of the less common sterols and of certain trans- formation products of cholesterol and ergosterol. The growing mass of data available concerning the exact structure of andro- genic and estrogenic compounds has led to much speculation as to the correlation of structure with function. Although all theories presented to date are subject to many damaging exceptions, a round-table discussion devoted to this subject proved productive of much speculative thinking. Dr. Fieser suggested the possible correla- tion of certain physical constants with relative biological activity. The trick, of course, would be to find the right physical constant. He cited a case in point from his wartime investigations of antimalarials, where it was found that in a certain group of anthraquinone derivatives antimalarial activity was regularly related to a dis- tribution constant established between ether and a buffered aqueous solution in a two-layer system. Shape as Determinant of Function Alfred L. Wilds of the University of Wisconsin who presided at the discussion suggested that perhaps the gross shape of steroid molecules was responsible for their function. This sort of theory has been advanced in relation to certain other biologically active compounds, notably the antihistamines. William Ruigh of Nopco Chemical Co. supported this viewpoint and suggested that perhaps the activity was due to specific oriented adsorption on a cellular or colloidal surface. In a later paper Leo T. Samuels of the University of Utah reported the successful enzymic metabolism of androgens by liver and kidney tissue in vitro. This metabolism required the presence of whole cells, which tends to support a theory of adsorption on the cell wall. Another suggestion offered was that the steroids react primarily with body pro- teins forming loose linkages through vari- ous active groups. Such combinations may result in either the activation or de- activation of the hormone substance. The most significant contribution to this round table, and perhaps to the entire meeting, was an announcement by Albert Wettstein of the Ciba Co., Ltd., Basel, Switzerland, that an 1 l-dehydroproges- terone produced in his laboratories had proved three times as active as natural progesterone when evaluated by certain tests on rabbits. The work on this new compound is still in the preliminary stage, however, so that its full significance cannot yet be established. One of the more interesting general papers of the meeting was presented by Konrad E . Bloch of the University of Chicago, who spoke on the biosynthesis of steroids. He pointed out that in the natural production of all steroid hormones in the bodily organs certain steps are analogous. It is believed that all such substances are derivatives of cholesterol, which is present in all body cells. This cholesterol apparently originates in the liver, where it is produced by an enzymic action of the whole cells. One of the pri- mary constituents of the reaction appears to be acetic acid. Although the field of steroid hormones has barely progressed beyond the purely empirical stage, it is hoped by the sponsors of this symposium that the meeting of minds among interested groups will do much to speed its development. How- ever, it was the consensus of the group that with the definite determination of al- most all of the structures of the active compounds and their structurally related molecules, the work of the organic chemist in this field is drawing lo a close and it is time for the biochemist, the physiologist, and the pharmacologist to put the knowl- edge offered to them to constructive use. VOLUME 2 6, NO. 39. SEPTEMBER 2 7, 1948 2891
Transcript of Mechanism of Steroid Hormone Activity Investigated
Λ. L. Wilds, University of Wisconsin; U. V. Sohnssen, Warner institute; and Louis Fieser, Flctrvai^I University, at meeting
Tf. W. Barrett, Colorado State College, and E. E. Hays, Armour Laboratories, trade notes
Mechanism of Steroid Hormone Activity Investigated A STAFF REPORT
XTL GREAT mass of new empirical d a t a was presented to about 200 organic and biochemists and physiologists in the field of steroid hormones a t a symposium sponsored by the University of Wisconsin a t Madison on Sept. 6 through 8. Although much time was devoted to discussion of the precise mechanism of steroid hormone act ivi ty and of the correlation of physical arid structural characteristics with physiological activity, there were few glimmers of light cast upon this exceedingly complex subject. However, in one of the prel iminary talks Louis F. Fieser of Harvard University reviewed the promising posit ive advancements which have been made in the last few years in determining t h e physical s tructure of the steroid compounds. Although some of the s t ruc tures advanced are still being questioned, t h e solution of the structural chemical pa r t of the problem seems imminent. He also quoted the recent adaptat ion of the new techniques of physical chemistry to biological problems. Some investigations with radioactive tracers have a l ready achieved results in the s tudy of endocrinological activity, particularly in t h e metabolism of cholesterol. Absorption spectroscopy has proved a par t icular^ ' effective tool because the significant conjugated polyene and ketone configurations produce adsorption in the ul traviolet while hydroxyl groups and isolated car-bonyl groups affect the near infrared a b sorption.
The determination of optical ac t iv i ty has also proved a rich source of information on structure and configuration a n d has been directly responsible for the s t ruc tural determination of a number of t he less common sterols and of certain t r ans formation products of cholesterol a n d ergosterol.
The growing mass of data available
concerning the exact structure of androgenic and estrogenic compounds has led to much speculation as to the correlation of structure with function. Although all theories presented to date are subject to many damaging exceptions, a round-table discussion devoted to this subject proved productive of much speculative thinking. Dr. Fieser suggested the possible correlation of certain physical constants with relative biological activity. The trick, of course, would be to find the r ight physical constant. He cited a case in point from his wart ime investigations of antimalarials, where it was found tha t in a certain group of anthraquinone derivatives antimalarial activity was regularly related to a distribution constant established between ether and a buffered aqueous solution in a two-layer system.
Shape as Determinant of Function
Alfred L. Wilds of the University of Wisconsin who presided at the discussion suggested t ha t perhaps the gross shape of steroid molecules was responsible for their function. This sort of theory has been advanced in relation to certain other biologically active compounds, notably the antihistamines. William Ruigh of Nopco Chemical Co. supported this viewpoint and suggested that perhaps the activity was due to specific oriented adsorption on a cellular or colloidal surface. In a later paper Leo T. Samuels of the University of Utah reported the successful enzymic metabolism of androgens by liver and kidney tissue in vitro. This metabolism required the presence of whole cells, which tends to support a theory of adsorption on the cell wall.
Another suggestion offered was t ha t the steroids react primarily with body proteins forming loose linkages through vari
ous active groups. Such combinations may result in either the ac t iva t ion or deactivation of the hormone substance.
T h e most significant contribution to this round table, and perhaps to the entire meeting, was an announcement by Albert Wet ts te in of the Ciba Co. , Ltd., Basel, Switzerland, that an 1 l-dehydroproges-terone produced in his laboratories had proved three times as ac t ive as natural progesterone when evaluated by certain tests on rabbits. The work on this new compound is still in the preliminary stage, however, so that its full significance cannot yet b e established.
One of the more interesting general papers of the meeting was presented by Konrad E . Bloch of the Universi ty of Chicago, who spoke on the biosynthesis of steroids. He pointed o u t tha t in the natural production of all s te ro id hormones in t h e bodily organs certain steps are analogous. I t is believed t h a t all such substances are derivatives of cholesterol, which is present in all body cells. This cholesterol apparently originates in the liver, where it is produced by an enzymic action of the whole cells. One of the primary constituents of the react ion appears to be acetic acid.
Although the field of s teroid hormones has bare ly progressed beyond the purely empirical stage, it is hoped by the sponsors of this symposium that the meeting of minds among interested groups will do much to speed its development. However, it was the consensus of the group that with the definite determination of almost all of the structures of the act ive compounds and their structurally related molecules, the work of the organic chemist in th is field is drawing lo a close and i t is time for t he biochemist, t h e physiologist, and the pharmacologist to pu t the knowledge offered to them to constructive use.
V O L U M E 2 6, N O . 3 9 . S E P T E M B E R 2 7, 1 9 4 8 2891
