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Diethylstilbestrol and Estradiol Binding to Serum Albumin and Pregnancy Plasma of Rat and Human*

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Diethylstilbestrol and Estradiol Binding to Serum Albumin and Pregnancy Plasma of Rat and Human* 0013-7227/79/1045-1442$02.00/0 Endocrinology Vol. 104, No. 5 Copyright © 1979 by The Endocrine Society Printed in U.S.A. Diethylstilbestrol and Estradiol Binding to Serum Albumin and Pregnancy Plasma of Rat and Human* DANIEL M. SHEEHAN AND MARK YOUNG Department of Health Education and Welfare, Food and Drug Administration, National Center for Toxicological Research, Jefferson, 72079; and the Department of Biochemistry, University of Arkansas Downloaded from https://academic.oup.com/endo/article/104/5/1442/2592405 by guest on 30 September 2021 for Medical Science, Little Rock, Arkansas 72201 ABSTRACT. The equilibrium binding of diethylstilbestrol with a-fetoprotein. This was verified by Scatchard plots of DES (DES) and 17/?-estradiol (E2) to plasma proteins has been char- and E2 binding to rat and human pregnancy plasma. High acterized. DES exhibits a 10- to 20-fold greater binding affinity affinity, low capacity binding was demonstrated with E2 but not index for bovine serum albumin and rat plasma than E2. As with DES. The significantly lower binding of DES suggests that expected, E2 gave high values for binding to plasma from preg- increased delivery of DES to the fetus may be at least partially nant mice or rats, reflecting the presence of a-fetoprotein. DES responsible for the transplacental toxicity and carcinogenicity of bound to these samples as it did to bovine serum albumin and DES. (Endocrinology 104: 1442, 1979) rat plasma. These results suggested that DES interacts weakly HE INTERACTION of hormones with blood pro- Materials and Methods Tteins is a significant determinant of hormonal po- tency. Such interactions influence metabolism, excretion, E2 was obtained from Research Plus Steroid Laboratories and availability to target tissues (See Refs. 1-3 for re- (Denville, NJ) and was used without further purification. DES, from Sigma Chemical Co. (St. Louis, MO), was essentially 100% views). Diethylstilbestrol (DES), a nonsteroidal estrogen, pure, as judged by high pressure liquid chromatography and is one of the more socially and economically important temperature-programmed gas chromatography. Labeled hor- synthetic hormones. It has been used extensively to 3 3 mones, [6,7- H]E2 (42 Ci/mmol) and [monoethyl-l- H]DES increase weight gain in cattle (4) and for treatment of (62.4 Ci/mmol), were obtained from New England Nuclear menopausal symptoms (5), postmenopausal breast can- (Boston, MA) and were repurified by Sephadex LH-20 chro- cer (6), and prostatic carcinoma (7). However, an asso- matography every 2 months to insure radiochemical purity (11). ciation between the administration of DES to pregnant The solvent system was benzene-methanol with ratios of 85:15 3 3 women and a marked increase in the occurrence of en- for [ H]E2 and 80:20 for [ H]DES. Sephadex (TM) G-25 (coarse) dometrial carcinoma in their offspring has been reported was obtained from Pharmacia (Sweden). All other chemicals (8). Additionally, a considerable body of evidence has were reagent grade or better. Blood was collected in heparinized tubes and centrifuged, accumulated from animal studies demonstrating a vari- and the plasma was stored in aliquots at —20 C. Rat and mouse ety of toxic (including carcinogenic) effects of DES (9, pregnancy plasma was collected from animals in the third 10). trimester of pregnancy. Human pregnancy plasma was obtained Despite these observations, the intraction of DES with from women in labor. Bovine serum albumin powder (fraction plasma proteins has not been well defined. Consequently, V; BSA) was supplied by ICN Pharmaceuticals (Irvine, CA). the possible role of such interactions in modulating the Protein determinations were carried out by the method of normal and toxic actions of DES is unclear. The results Lowry et al. (12) using BSA as the standard. described here demonstrate large differences in the bind- The binding of radiolabeled hormones to plasma or BSA was 3 ing of DES and 17/?-estradiol (E2) to serum albumin, measured by a gel equilibration technique (13). Briefly, [ H]E2 3 plasma and the pregnancy-associated proteins, rat a-fe- or [ H]DES (about 100,000 cpm) was added to 200 mg Sephadex toprotein (aFP), and human testosterone-estradiol-bind- G-25 (preswollen in 1 ml 0.155 M sodium phosphate, pH 7.4) in 1.5 X 4.5-cm glass vials. Other components, including protein ing globulin (TEBG). solution and nonradioactive carrier, were added to give a final B Received June 21,1978. volume of 2.0 ml. The partitioning of DES and E2 (5 X 10~ M Address requests for reprints to: Dr. Daniel M. Sheehan, National to about 2 X 10"10 M) in the absence of protein was independent Center for Toxicological Research, Jefferson, Arkansas 72079. of hormone concentration. At least three such determinations * This work was presented in part at the Third Annual National Research Center for Toxicological Hormone Research Symposium, were included in every experiment. After incubation for 1 h at November 15-17,1976, Little Rock, AR. 22 C with gentle shaking, the samples were incubated undis- 1442 E2 AND DES BINDING TO PLASMA PROTEINS 1443 turbed for 30 min to allow complete settling of the Sephadex. Results Duplicate aliquots (200 /xl) were then dissolved in Scintiverse (Fisher Scientific, Pittsburgh, PA), and the samples were Initial determination of the equilibrium binding of E2 counted in a Packard Tricarb liquid scintillation counter. The and DES to BSA and various plasmas were carried out amount of unbound (Su) and bound (Sb) hormone was calcu- by the gel equilibration method described by Pearlman lated via a computer program. In this assay, hormone partitions and Crepy (13). In this procedure, a fixed amount of between the external and internal volumes of the Sephadex, steroid is titrated with an increasing concentration of while protein is restricted to the external volume. The amount of hormone in the external volume above protein-free controls protein. The reciprocal of the protein concentration at is a measure of binding. The work of Pearlman and Crepy (13) which the Su:Sb ratio is unity is determined at several provides details of the theory and data reduction for this assay. input steroid concentrations (Fig. 1). The data derived from a group of such experiments are then plotted, as Downloaded from https://academic.oup.com/endo/article/104/5/1442/2592405 by guest on 30 September 2021 shown in Fig. 2. The lines for the binding of E2 to pooled adult rat plasma, 1-month-old female rat plasma, and 10 Sb=l.O»lO M BSA show no apparent concentration dependence, and a binding affinity index (value for the reciprocal of the protein concentration at Su:Sb = 1) of about 1. These data indicate that normal plasma and BSA possess only one class of low affinity, high capacity sites for E2. DES, however, shows a significantly higher affinity (10- to 20- I/P (I/O) fold) than E2 for these samples. Additionally, the slight concentration dependence of binding suggests the possi- Sb = I.ii x io« M bility of site heterogeneity. I/P=O.«S L/C The binding of E2 and DES to rat and mouse preg- nancy plasma was also investigated. In addition to albu- min, these plasmas are known to contain aFP, which has high affinity for E2 (14-18). Such high affinity sites are demonstrated by the significant slope of E2 binding to 71 pregnancy plasmas (Fig. 2). However, the binding of DES I/P (I/O) to these samples was identical to the DES binding to FlG. 1. Calculation of binding affinity for E2 binding to plasma. Plasma BSA and plasma from nonpregnant animals. Thus, DES from 20-day-old female rats was titrated against fixed concentrations of does not appear to bind with high affinity to rodent aFP. 3 [ H]E2. The input E2 concentrations in panels A-E were, respectively, The low affinity binding observed with DES and BSA 1.18 x 1(T9, 1.12 x :i(T8,1.01 X 10~7,1.00 x 10"6, and 1.00 x 10~5 M. The concentration of Sb at an Su:Sb ratio of 1 as well as the value for the was further characterized by Scatchard (19) analysis (Fig. reciprocal of the protein concentration (1/P) required to achieve that 3). At least two classes of low affinity, high capacity sites 6 6 ratio is shown in each panel. on BSA [Kdi = 4 x 10~ M (ih = 3) and Kd2 = 9.5 x 10" 100 FIG. 2. The binding of E2 and DES to various plasma samples and BSA. Values of the reciprocal of the protein concen- 10 tration (1/P) and the concentration of bound steroid at Su:Sb = 1 were deter- mined, as described in Fig. 1, for each of the samples. The data are plotted on a log-log scale, according to Pearlman and Crepy (12). Pooled adult rat plasma: E2 (O), DES [not determined (N.D.)]; preg- nant mouse plasma: E2 (D), DES (•); pregnant rat plasma: E2 (A), DES (A); 28-day-old female rat plasma: E2 (V), DES (•); BSA: E2 (+), DES (X). 106 10' 10" 10* 101 1/Sb (M) 1444 SHEEHAN AND YOUNG Kntlo i 1979 Vol 104 , No 5 M (n2 = 12)] are found by graphical resolution (20). It should be noted that these studies were carried out up to the solubility limits of DES in aqueous solution. The 2.0 solubility of DES under the experimental conditions was first determined in the absence of protein and was the limiting value used, since protein binding can increase the apparent solubility of hormones. It is not possible, however, to obtain a reliable Scatchard plot for E2 bind- ing to BSA because of the insolubility of E2 over a major 1.0 portion of the necessary concentration range.
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