Abstract

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 K_m and k_cat 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, k_cat/K_m, 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.