title: Metabolism of 2 alpha-propoxy-1 alpha,25-dihydroxyvitamin D3 and 2 alpha-(3-hydroxypropoxy)-1 alpha,25-dihydroxyvitamin D3 by human CYP27A1 and CYP24A1.
abstract: Recently, we demonstrated that some A-ring-modified vitamin D3 analogs had unique biological activity. Of these analogs, 2alpha-propoxy-1alpha,25(OH)2D3 (C3O1) and 2alpha-(3-hydroxypropoxy)-1alpha,25(OH)2D3 (O2C3) were examined for metabolism by CYP27A1 and CYP24A1. Surprisingly, CYP27A1 catalyzed the conversion from C3O1 to O2C3, which has 3 times more affinity for vitamin D receptor than C3O1. Thus, the conversion from C3O1 to O2C3 by CYP27A1 is considered to be a metabolic activation process. Five metabolites were detected in the metabolism of C3O1 and O2C3 by human CYP24A1 including both C-23 and C-24 oxidation pathways. On the other hand, three metabolites of the C-24 oxidation pathway were detected in their metabolism by rat CYP24A1, indicating a species-based difference in the CYP24A1-dependent metabolism of C3O1 and O2C3 between humans and rats. Kinetic analysis revealed that the Km and kcat values of human CYP24A1 for O2C3 are, respectively, approximately 16 times more and 3 times less than those for 1alpha,25(OH)2D3. Thus, the catalytic efficiency, kcat/Km, of human CYP24A1 for O2C3 is only 2% of 1alpha,25(OH)2D3. These results and a high calcium effect of C3O1 and O2C3 in animal experiments using rats suggest that C3O1 and O2C3 are promising for clinical treatment of osteoporosis.
authors.affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Abe
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakaki
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kusudo
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kittaka
authors.forename: Nozomi
authors.initials: N
authors.lastname: Saito
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Suhara
authors.forename: Toshie
authors.initials: T
authors.lastname: Fujishima
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Takayama
authors.forename: Hiromi
authors.initials: H
authors.lastname: Hamamoto
authors.forename: Masaki
authors.initials: M
authors.lastname: Kamakura
authors.forename: Miho
authors.initials: M
authors.lastname: Ohta
authors.forename: Kuniyo
authors.initials: K
authors.lastname: Inouye
mesh_terms: D000818:Animals; D002417:Cattle; D053493:Cholestanetriol 26-Monooxygenase; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004100:Dihydroxycholecalciferols / Q000737:chemistry* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D051381:Rats; D013045:Species Specificity; D013250:Steroid Hydroxylases / Q000378:metabolism*; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D004100:Dihydroxycholecalciferols; D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; C585549:CYP24A1 protein, human; C585551:Cyp24a1 protein, rat; D065668:Vitamin D3 24-Hydroxylase