title: A stable epoxide of estrone: Evidence for formation of a 'new' estrogen metabolite.
abstract: Oxidative metabolism of estrogens is an important feature in liver and some non-hepatic tissues. In initial studies on estrogen metabolism in tissues from the reproductive tract of the stallion, where testicular estrogen secretion is remarkably high, a prominent radiolabeled product from [3H]-estrone (E1) was noted on chromatography; it had a retention time (Rt) between 17β-estradiol (E2) and E1. Unexpectedly, when non-radiolabeled E1 was the substrate no UV absorption at 280nm was seen at the Rt for the [3H]-labeled product-suggesting a non-aromatic ring A. The following efforts were made to reveal more about the nature of the "unknown" compound. Reduction and acetylation showed, separately, the presence of a single keto and hydroxyl group. Exposure to acid gave a single radiolabeled peak with Rt of 6α-hydroxy-E1-suggesting the presence of a third molecule of oxygen. Mass spectrometry with limited material was inconclusive but supportive for a formula of C18H22O3.Thus, an epoxide involving the aromatic ring of E1 is suggested as a labile intermediate in the formation of the "unknown" metabolite. Estrogen epoxides as labile, reactive intermediates have been considered as potential precursors of the 2- and 4-hydroxy catechol estrogens with implications in breast cancer [Soloway, 2007]. Because of the association of the "unknown" metabolite with 6α-hydroxy-E1, the structural form proposed for the stable epoxide is that for 5α,6α-epoxy-estrone. This represents an alternative to the production of the 2- and 4-hydroxy-catechol estrogens. The broad range in normal tissues where the "unknown" compound was shown to be a persistent metabolite (e.g. mouse mammary glands, ovary, uterus, brain, muscle, equine conceptus, stallion and domestic boar reproductive tracts) suggests more general biological implications.
authors.affiliation: Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada. Electronic address: jraeside@uoguelph.ca.
authors.forename: James I
authors.initials: JI
authors.lastname: Raeside
authors.affiliation: Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Christie
mesh_terms: D000818:Animals; D002396:Catechols / Q000737:chemistry; D002845:Chromatography; D002851:Chromatography, High Pressure Liquid; D004852:Epoxy Compounds / Q000737:chemistry*; D004958:Estradiol / Q000737:chemistry; D004967:Estrogens / Q000737:chemistry; D004970:Estrone / Q000031:analogs & derivatives* / Q000737:chemistry*; D005260:Female; D006736:Horses; D006868:Hydrolysis; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D010100:Oxygen / Q000737:chemistry; D013056:Spectrophotometry, Ultraviolet; D034421:Sus scrofa; D013552:Swine; D014466:Ultraviolet Rays
chemical_list: C000620961:5,6-epoxyestrone; D002396:Catechols; D004852:Epoxy Compounds; D004967:Estrogens; D004970:Estrone; D004958:Estradiol; D010100:Oxygen
keywords: 6α-Hydroxy-estrone; Epoxide; Estrone; Radioactive steroids; Stable metabolite; Tissue incubations