The compound 2-methyl-1: 2-bis-(3-pyridyl)-1-propanone (SU 4885) is now widely used in testing the reserve capacity of the pituitary gland to secrete adrenocorticotrophic hormone. In the opinion of Liddle, Estep, Kendall, Jr., Carter Williams, Jr. & Townes (1959) it is a relatively specific inhibitor of 1 1 \ g = b \ -h y d r o x y l a t i o n . This view has been supported by experimental and clinical evidence. For instance, Grant (1960) showed that SU 4885 decreased 1 1 \ g = b \ -h y d r o x y l a s e activity, but left the 17-and 21-hydroxylating enzymes unaffected.Recently, however, results have accumulated that throw doubt on the specific inhibitory action of SU 4885 on 1 1 \ g = b \ -h y d r o x y l a t i o n .Loraine (1962) found that SU 4885 administered in high doses caused a decrease in steroid formation which was greater than inhibition of 1 1 \ g = b \ -h y d r o x y l a t i o n alone could account for. Venning, Lucis, Dyrenfurth & Beck (1962) showed that the drug increased the urinary excretion of pregnandiol. Grant (1960) raised the point that SU 4885 may have a direct stimulatory effect on 11-deoxycortisol formation in the adrenal gland and Ganong & Gold (1960) suggested a direct effect on the hypothalamo-hypophysial system.In the present work, nine healthy women were each given a 24 hr. course of 3-0 g. of SU 4885 (Metopiron, CIBA) administered orally in doses of 500 mg. every 4 hr. Complete 24 hr. collections of urine were made on the day before, during, and on the day after treatment. Urinary oestrogens were determined by the method of Steczek & Koref (1963).The effects of SU 4885 on urinary oestrogen values are summarized in Table 1. All subjects showed marked decreases in oestradiol excretion (P < 0-001), certainly more considerable than could have occurred during the observation period without the drug. The decreases in oestriol and oestrone excretion were less marked in most subjects. Two possibilities can be adduced to explain the decreases in the excretion of oestra¬ diol : decreased oestradiol formation or accelerated oestradiol metabolism. We incline to the view that the former is the more valid explanation. Griffiths (1963) has recently shown that, in addition to producing an inhibitory effect on ll/?-hydroxylase, SU 4885 inhibits 19-hydroxylation. The latter plays a major role in oestradiol forma¬ tion (Longchampt, Gual, Ehrenstein & Dorfman, 1960), for in the steroid ring A hydroxylation at C19 is the first stage in aromatization. It seems likely that, when hydroxylation is inhibited, less A4-androstene-3 :17-dione is converted to oestradiol and that, instead, other ll-deoxy-17-oxosteroids are produced. This concept is sup¬ ported by the observation (Foldes, Koref, Fehér, Steczek & Krasznai, 1963) that a fall in urinary oestradiol is accompanied by increases in both androsterone and aetiocholanolone excretion. The marked effect of SU 4885 raises the interesting possi¬ bility that the compound exerts not only a selective effect on the adrenal cortex but
F\l=O"\LDES 19-Hydroxylation of the steroid molecule is an obligatory step in the conversion of androgens to oestrogens. It has been shown (F\l=o"\ldes,Koref, Feh\l=e'\r & Steczek, 1964) that the urinary excretion of individual oestrogens decreases after the administration of 2-methyl-1,2-bis-(3-pyridyl)-1-propanone (SU4885).The aim of the present communication is to show that SU 4885 inhibits the transformation of androstenedione to oestrogens in the rat ovary in vitro. The following trivial names are used: androstenedione = androst-4-ene-3,17-dione; oestradiol = oestra-1,3,5(10)-triene-3,17\g=b\-diol; oestrone = 3-hydroxy-oestra-1,3,5(10)-trien-17\x=req-\ one.Female rats of the Wistar strain, weighing 180\p=n-\250 g., received two injections of 50 units chorionic gonadotrophin (HCG, Choriogonin, Richter, Budapest) 24 and 16 hr. before the ovaries were removed. For each assay, 18 animals were used, six of which also received s.c. 10 mg. SU 4885 (Metopirone, Ciba, Basel) 40, 24 and 16 hr. before death. The ovaries were removed, halved and distributed (12 halved ovaries, 250-350 mg./vessel) between six vessels each containing 5\m=.\0ml. Krebs\p=m-\Ringer phosphate solution, pH 7\m=.\4.Tissue from the SU4885-treated animals was placed in vessels 3 and 4. Androstenedione, 25 pig. in 0-1 ml. propylene glycol, was added to vessels 2, 4 and 6 and propylene glycol only to the remaining three, which then served as controls. SU4885 (20 pig.) was also added to vessels 5 and 6. Incubations lasted for 3 hr. at 37°in 95 % 02:5 % C02.After incubation, the contents were homogenized and extracted three times with 15 ml. peroxide-free ether. The combined extracts were washed with 5 ml. water, dried over anhydrous'Na2S04 and the ether evaporated. Thin-layer chromatography was used for purification and separation of the oestrogens. The extracts and 0-25, 0-5 and 1-0 pig. of oestradiol and oestrone (for a standard curve) were applied to 1 cm. strips of Kieselgel G chromatoplate (layer thickness 250 pi), equilibrated for 20 min., developed for 2 hr. in freshly distilled chloroform for purification and for separation in the system benzene : absolute ethanol (95:5). The zones containing oestradiol and oestrone were located from a reference strip, scraped off, and Ittrich's (1958) colour reaction performed in the presence of the adsorbent. Oestradiol and oestrone were determined by means of calibration curves.
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