title: Synthesis and biological activities of 1α,4α,25- and 1α,4β,25-trihydroxyvitamin D(3) and their metabolism by human CYP24A1 and UDP-glucuronosyltransferase.
abstract: A previous report has demonstrated the existence of a C4-hydroxylated vitamin D(2) metabolite in serum of rats treated with pharmacological doses of vitamin D(2). However, the biological significance and metabolic fate of this metabolite have not been described. To explore its potential biological activities, we therefore synthesized 1α,4α,25-trihydroxyvitamin D(3) and its diastereoisomer, 1α,4β,25-trihydroxyvitamin D(3), using Trost Pd-mediated coupling reaction, and studied their vitamin D receptor (VDR) binding affinity, osteocalcin promoter transactivation activity, and their further metabolism by human CYP24A1 as well as by human liver microsomal fraction based on CYP- and UDP-glucuronosyltransferases (UGTs)-reactions.
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University, Tokyo 173-8605, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sawada
authors.forename: Yuya
authors.initials: Y
authors.lastname: Tsukuda
authors.forename: Kaori
authors.initials: K
authors.lastname: Yasuda
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Saito
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Takagi
authors.forename: Kazuya
authors.initials: K
authors.lastname: Takenouchi
authors.forename: Tai C
authors.initials: TC
authors.lastname: Chen
authors.forename: G Satyanarayana
authors.initials: GS
authors.lastname: Reddy
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kittaka
mesh_terms: D002460:Cell Line; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D006887:Hydroxycholecalciferols / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000378:metabolism; D015675:Osteocalcin / Q000235:genetics; D018167:Receptors, Calcitriol / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D006887:Hydroxycholecalciferols; D018167:Receptors, Calcitriol; D015675:Osteocalcin; D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; C585551:Cyp24a1 protein, rat; D065668:Vitamin D3 24-Hydroxylase; D014453:Glucuronosyltransferase