Donald S. Layne

Metabolic clearance rates and interconversions of estrone and 17β-estradiol in normal males and females

The continuous infusion of (3)H-6,7-estrone and (3)H-6,7-estradiol has been used to study the metabolic clearance rate (MCR), the interconversions, and the red cell uptake of these steroids in normal males and females. The whole blood MCR of estrone is 1,990 +/- 120 liters per day/m(2) (SE) in males and 1,910 +/- 100 liters per day/m(2) in females. The whole blood MCR of estradiol is 1,600 +/- 80 liters per day/m(2) in males and 1,360 +/- 40 liters per day/m(2) in females. The values in females do not vary significantly when studied in the follicular or luteal phase of the cycle. At least 35% of the total estrone metabolism in both sexes is extrasplanchnic and at least 25% of the total estradiol metabolism in males, and 15% in females is extrasplanchnic. The [rho](BB) (2,1) [transfer constant of estradiol to estrone, which is equivalent to the fraction of the precursor (estradiol) converted to the product (estrone) when both the infusion of the precursor and the measurement of the product are in peripheral blood] is 15%; and the [rho](BB) (1,2) [transfer constant of estrone to estradiol, which is equivalent to the fraction of the precursor (estrone) converted to product (estradiol) when both the infusion of the precusor and the measurement of the product are in peripheral blood] is 5% in both males and females. Our findings concerning the radioactivity in whole blood, as measured by our procedure, were the following: 15-20% of estrone in both sexes and 15% of estradiol in males is associated with red cells. Only 2% of the whole blood radioactivity of estradiol in females is associated with red cells. Changes in the distribution of radioactivity between plasma and red cells will influence the MCR as calculated from plasma, but not as calculated from whole blood.

THE BINDING OF ALDOSTERONE TO PLASMA PROTEINS IN NORMAL, PREGNANT, AND STEROID-TREATED WOMEN*

There is now abundant evidence that both cortisol and corticosterone are bound in plasma to a protein with high affinity and low capacity (probably an a-globulin termed transcortin) as well as to albumin (1-10). It has also been shown that either the concentrations of transcortin or its affinity for cortisol is increased in pregnancy and after estrogen treatment (4, 10), although one group (10) has not found increased binding of tracer amounts of cortisol in pregnancy. Preliminary studies by Mills, Chen and Bartter (7, 8) indicated that aldosterone is bound to proteins other than albumin to a much lesser extent than is cortisol. Sandberg, Slaunwhite and Carter (9) reported an appreciable binding of aldosterone in diluted plasma dialyzed against albumin at 40 C. The aldosterone was readily displaced from the binding protein by the addition of cortisol, while cortisol binding under similar conditions was not significantly reduced by the addition of physiological amounts of aldosterone (9). During the preparation of this manuscript Daughaday, Holloszy and Mariz (10) reported that at 370 C they could not demonstrate any binding of aldosterone to proteins other than albumin in the plasma of normal women or in that of pregnant subjects and women treated with estrogen, but they found appreciable binding of aldosterone to such a protein in normal plasma at 40 C. The present paper gives detailed data on the binding of aldosterone in normal plasma, obtained by a microdialysis technique with 7-H3aldosterone of high specific activity (20 fsc per pg). Plasma from pregnant subjects and from

Metabolism of dimethyl sulfide, dimethyl sulfoxide, and dimethyl sulfone in the rabbit

Abstract The subcutaneous injection of either dimethyl sulfide or dimethyl sulfoxide leads to the excretion of dimethyl sulfoxide and dimethyl sulfone in the urine of rabbits and to the expiration of a malodorous material (presumably dimethyl sulfide). Dimethyl sulfone, however, is not reduced to either the sulfoxide or the sulfide but is excreted unchanged. Dimethyl sulfone is also found in the urine of untreated rabbits.

The metabolic fate of orally administered 3H-norethynodrel and 3H-norethindrone in humans☆

Abstract The excretion of radioactivity in the urine of four women, after oral administration of tritiated 17α-ethynyl-estr-5(10)-ene-3-one-17β-o1 (norethynodrel) averaged 38 per cent of the administered dose. Two women receiving oral doses of tritiated 17α-ethynyl-19-nortestosterone (norethindrone) excreted, respectively, 70 and 50 per cent of the dose in their urine, 30 per cent of the dose of 3 H-norethynodrel was found in bile collected from one subject. Thirty to sixty per cent of the radioactivity in the urine of subjects receiving either 3 H-norethynodrel or 3 H-norethindrone was conjugated as glucosiduronate and another 9 to 25 per cent was another conjugate, presumably sulfate. Some evidence was obtained on the nature of the conversion products of norethynodrel in the glucosiduronate fraction of the urine of two women. These were mainly steroid alcohols, all but one of which carried the ethynyl side chain. Only traces of ketosteroids were present, and no evidence was found of major conversion of norethynodrel to phenolic compounds.

Oxidation of Dimethyl Sulfoxide to Dimethyl Sulfone in the Rabbit

A white, crystalline compound was obtained from a butanol extract of the urine of rabbits injected subcutaneously with dimethyl sulfoxide. The melting point and infrared spectrum of the compound were identical with those of authentic dimethyl sulfone.

Further studies on the nature of phenolic steroids in the rabbit and their mode of conjugation

Abstract The injection of large quantities of the dipropionate of 17β-estradiol-6,7- 3 H into a normal and an ovariectomized-hysterectomized rabbit led in both instances to excretion of the radioactivity as estradiol-3-glucuronoside-17α- N -acetylglucosaminide. No radioactive estrone or estriol was detected in the urine in either a free or conjugated form. In a male rabbit, administered 17β-estradiol-4- 14 C was also excreted almost entirely as the double glycoside of 17α-estradiol, indicating that formation of this conjugate is not sex dependent. Evidence was obtained by optical rotation measurements that both the N -acetylglucosamine and the glucosiduronic acid are attached to the excreted 17α-estradiol by β-glycosidic linkages, provided that the sugars are assumed to be of the d -configuration.

SOME BIOLOGICAL PROPERTIES OF A URINARY NORETHYNODREL METABOLITE.

Summary Estrogenic activity of 17α-ethynyl-19-norandrost-4-ene-3β,10β,17β,-triol, a urinary metabolite of norethynodrel, was investigated. The compound exhibited slight estrogenicity when administered subcutaneously. Gavage resulted in increased estrogenicity. Within a limited dose range, injection of the compound together with estrone resulted in synergistic estrogenic activity.

Transfer of Glucose to Phenolic Steroids and Possible Physiological Role of the Glucosides

Publisher Summary Over the past fifteen years, a series of novel glycosides of the steroid estrogens have been isolated in laboratories from the urine and bile of rabbits and of humans. These have included 2-acetamido-2-deoxyglucosides and glucosides, and it has been shown that these sugars could be transferred in vivo from their respective uridine nucleotides to the steroids by liver microsomal preparations. Glucose and galactose can be transferred, under appropriate conditions, to OH-3 to form monoglycosides. The evidence for the involvement of a lipid intermediate in the synthesis of the steroid glucosides is as follows: (1) liver microsomes can form significant amounts of these compounds in the absence of added UDP-glucose and of detectable amounts of endogenous UDP-glucose and (2) the chloroform–methanol or chloroform–methanol–water extracts of rabbit or pig liver enhance the synthesis. The evidence that has been obtained indicates that the formation of the estrogen glucosides facilitates the passage of the steroid through the outer membrane of the liver cell.

REACTIVITY OF THE THALLIUM(I) SALTS OF 3‐HYDROXY‐1,3,5(10)‐ESTRATRIEN‐17‐ONE AND 1,3,5(10)‐ESTRATRIENE‐3,17BETA‐DIOL, PREPARATION OF 17‐OXOESTRA‐1,3,5(10)‐TRIEN‐3‐YL 2′‐ACETAMIDO‐3′,4′,6′‐TRI‐O‐ACETYL‐2′‐DEOXY‐BETA‐D‐GLUCOPYRANOSIDE

Thallium(I) salts of estrone and 17β-estradiol were prepared in high yields by the reaction of estrone or 17β-estradiol with thallium(I) ethoxide. Both compounds were found to be reactive intermediates for alkylation and acylation of the steroid. The preparation and characterization of 17-oxoestra-1,3,5(10)-trien-3-yl 2′-acetamido-2′-deoxy-β-D-glucopyranoside by reaction of the thallium(I) salt of estrone with 2-trifluoroacetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranosyl bromide is described.