title: Chemical synthesis of six novel 17beta-estradiol and estrone dimers and study of their formation catalyzed by human cytochrome P450 isoforms.
abstract: Our earlier studies have shown that over 20 nonpolar 17beta-estradiol metabolite peaks were detected following incubations of radioactive 17beta-estradiol with human liver microsomes or recombinant human cytochrome P450 isoforms in the presence of NADPH as a cofactor. The structures of two representative nonpolar metabolites were identified earlier as dimers of 17beta-estradiol linked through a diaryl ether bond between the C-3 phenolic oxygen of one molecule and the C-2 or C-4 aromatic carbon of another. Six additional putative dimers between estrone and 17beta-estradiol with structures similar to the two identified ones were synthesized in this study. Using these newly synthesized estrogen dimers as reference standards, we demonstrated that incubations of human liver microsomes or various human cytochrome P450 isoforms with estrone or 17beta-estradiol alone or two estrogens in combination in the presence of NADPH as a cofactor resulted in the formation of all eight estrogen dimers in varying quantities.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, School of Medicine, University of Kansas Medical Center, 2146 West 39th Street, Kansas City, Kansas 66160, USA.
authors.forename: Aaron Yun
authors.initials: AY
authors.lastname: Chen
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Lee
authors.forename: Xiang-Rong
authors.initials: XR
authors.lastname: Jiang
authors.forename: Bao Ting
authors.initials: BT
authors.lastname: Zhu
mesh_terms: D002384:Catalysis; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism*; D019281:Dimerization; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D004967:Estrogens / Q000737:chemistry / Q000378:metabolism*; D004970:Estrone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry
chemical_list: D004967:Estrogens; D007527:Isoenzymes; D011994:Recombinant Proteins; D004970:Estrone; D004958:Estradiol; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human