title: Estrogenic activity in vivo and in vitro of some diethylstilbestrol metabolites and analogs.
abstract: The diethylstilbestrol (DES) metabolite (beta-dienestrol), which had been identified in mouse, rat, monkey, and human urine, and two proposed metabolic intermediates (diethylstilbestrol alpha,alpha'-epoxide and alpha,alpha'-dihydroxy DES) were synthesized and their estrogenic activities determined. In addition, three DES analogs, alpha-dienestrol, DES-dihydroxy diethyl phenanthrene (DES-phenanthrene), and 1-(alpha-ethyl, 4alpha-hydroxyphenyl)indanyl-5-ol (indanyl-DES), were studied. Estrogenic activities of the compounds in vivo were determined by the immature mouse uterine weight bioassay; in vitro, their estradiol receptor binding activity (competitive equilibrium binding, sucrose gradient analysis, and association rate inhibition assays) was determined. Results of the mouse uterine weight bioassay gave the following order of estrogenicity: DES > alpha-dienestrol >/= DES-epoxide > indanyl-DES > dihydroxy DES > beta-dienestrol > DES-phenanthrene. Results of competitive equilibrium binding analyses of these compounds with estradiol-17beta for the mouse uterine cytosol receptor followed the same order seen for the bioassay, except for indanyl-DES. DES, indanyl-DES, and alpha-dienestrol had the greatest affinities (K(a) values approximately 0.5-19.1 x 10(10) M(-1)), while DES-phenanthrene had the lowest (K(a) = 3.5 x 10(7) M(-1) +/- 1.2). Sucrose gradient analysis of the above competition preparations illustrated the displacement of [(3)H]estradiol from the receptor peak. This displacement was receptor specific and concentration dependent and correlated with the equilibrium binding concentrations. In addition, the most hormonally active substances demonstrated the greatest rate inhibition in the estradiol cytosol receptor association rate reaction (V(0)). The rank order of estrogenicity of the compounds determined in this study should be useful in evaluating alternative metabolic pathways of DES as well as distinguishing biologically active metabolites from relatively inactive ones.
mesh_terms: D001667:Binding, Competitive; D004054:Diethylstilbestrol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004958:Estradiol / Q000378:metabolism; D005260:Female; D009929:Organ Size / Q000187:drug effects; D011960:Receptors, Estrogen / Q000378:metabolism; D013329:Structure-Activity Relationship; D014599:Uterus / Q000187:drug effects
chemical_list: D011960:Receptors, Estrogen; D004958:Estradiol; D004054:Diethylstilbestrol
references.citation: J Toxicol Environ Health. 1977 Jan;2(3):527-37
references.pmid: 846001
references.citation: J Toxicol Environ Health Suppl. 1976;1:37-44
references.pmid: 11352
references.citation: J Toxicol Environ Health Suppl. 1976;1:21-35
references.pmid: 994232
references.citation: Obstet Gynecol Surv. 1976 Nov;31(11):827-33
references.pmid: 980278
references.citation: N Engl J Med. 1971 Apr 15;284(15):878-81
references.pmid: 5549830
references.citation: Biochemistry. 1974 Apr 23;13(9):1932-8
references.pmid: 4365251
references.citation: Endocrinology. 1974 Mar;94(3):785-93
references.pmid: 4360477
references.citation: J Steroid Biochem. 1975 Mar-Apr;6(3-4):469-73
references.pmid: 241884
references.citation: Annu Rev Biochem. 1972;41:203-30
references.pmid: 4563437
references.citation: Endocrinology. 1975 Jul;97(1):231-6
references.pmid: 166831
references.citation: J Pharmacol Exp Ther. 1976 Jun;197(3):687-96
references.pmid: 819646
references.citation: J Am Chem Soc. 1976 May 26;98(11):3262-7
references.pmid: 1262645