title: Metabolism of 26,26,26,27,27,27-F6-1 alpha,23S,25-trihydroxyvitamin D3 by human UDP-glucuronosyltransferase 1A3.
abstract: 26,26,26,27,27,27-Hexafluoro-1alpha,25-dihydroxyvitamin D(3) [F(6)-1alpha, 25(OH)(2)D(3)], which is now clinically used as a drug for secondary hyperparathyroidism, is a hexafluorinated analog of the active form of vitamin D(3). Our previous studies demonstrated that CYP24A1 is responsible for the metabolism of F(6)-1alpha,25(OH)(2)D(3) in the target tissues and that F(6)-1alpha,25(OH)(2)D(3) was successively converted to F(6)-1alpha,23S,25(OH)(3)D(3) and F(6)-23-oxo-1alpha,25(OH)(2)D(3). In this study, we examined the metabolism of F(6)-1alpha,25(OH)(2)D(3),F(6)-1alpha,23S,25(OH)(3)D(3), and F(6)-23-oxo-1alpha,25(OH)(2)D(3) by human UDP-glucuronosyltransferases (UGTs). Of these compounds, F(6)-1alpha,23S,25(OH)(3)D(3) was remarkably glucuronidated both in human liver microsomes and in the recombinant system expressing human UGT. No significant interindividual differences were observed among 10 human liver samples. The recombinant system for 12 species of human UGTs revealed that F(6)-1alpha,23S,25(OH)(3)D(3) glucuronidation was specifically catalyzed by UGT1A3. The information obtained in this study seems very useful to predict the metabolism and efficacy of vitamin D analogs in human bodies before clinical trials. In addition, note that for the first time a possible probe substrate for UGT1A3 has been found.
authors.affiliation: Division of Food Science and Biotechnology, Gaduate School of Agriculture, Kyoto University, Kyoto, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kasai
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakaki
authors.forename: Raku
authors.initials: R
authors.lastname: Shinkyo
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Ikushiro
authors.forename: Takashi
authors.initials: T
authors.lastname: Iyanagi
authors.forename: Miho
authors.initials: M
authors.lastname: Ohta
authors.forename: Kuniyo
authors.initials: K
authors.lastname: Inouye
mesh_terms: D002117:Calcitriol / Q000031:analogs & derivatives* / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008862:Microsomes, Liver / Q000737:chemistry / Q000201:enzymology*
chemical_list: D007527:Isoenzymes; C077906:26,26,26,27,27,27-hexafluoro-1,23,25-trihydroxyvitamin D3; C122075:UDP-glucuronosyltransferase, UGT1A3; D014453:Glucuronosyltransferase; D002117:Calcitriol