TY - JOUR T1 - METABOLISM OF 2α-PROPOXY-1α,25-DIHYDROXYVITAMIN D<sub>3</sub> AND 2α-(3-HYDROXYPROPOXY)-1α,25-DIHYDROXYVITAMIN D<sub>3</sub> BY HUMAN CYP27A1 AND CYP24A1 JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 778 LP - 784 DO - 10.1124/dmd.104.003038 VL - 33 IS - 6 AU - Daisuke Abe AU - Toshiyuki Sakaki AU - Tatsuya Kusudo AU - Atsushi Kittaka AU - Nozomi Saito AU - Yoshitomo Suhara AU - Toshie Fujishima AU - Hiroaki Takayama AU - Hiromi Hamamoto AU - Masaki Kamakura AU - Miho Ohta AU - Kuniyo Inouye Y1 - 2005/06/01 UR - http://dmd.aspetjournals.org/content/33/6/778.abstract N2 - Recently, we demonstrated that some A-ring-modified vitamin D3 analogs had unique biological activity. Of these analogs, 2α-propoxy-1α,25(OH)2D3 (C3O1) and 2α-(3-hydroxypropoxy)-1α,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 1α,25(OH)2D3. Thus, the catalytic efficiency, kcat/Km, of human CYP24A1 for O2C3 is only 2% of 1α,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. The American Society for Pharmacology and Experimental Therapeutics ER -