Chemical Synthesis Of Side-Chain-Hydroxylated Vitamin D-3 Derivatives And Their Metabolism By Cyp27b1

1 alpha,25-Dihydroxyvitamin D-3 (abbreviated here as 1,25D(3)) is a hormonally active form of vitamin D-3 (D-3), and is produced from D-3 by CYP27 A1-mediated hydroxylation at C25, followed by CYP27B1-mediated hydroxylation at C1. Further hydroxylation of 25D(3) and 1,25D(3) occurs at C23, C24 and C26 to generate corresponding metabolites, except for 1,25R,26D(3). Since the capability of CYP27B1 to hydroxylate C1 of side-chain-hydroxylated metabolites other than 23S,25D(3) and 24R,25D(3) has not been examined, we have here explored the role of CYP27B1 in the C1 hydroxylation of a series of side-chain-hydroxylated D-3 derivatives. We found that CYP27B1 hydroxylates the R diastereomers of 24,25D(3) and 25,26D(3) more effectively than the S diastereomers, but shows almost no activity towards either diastereomer of 23,25D(3). This is the first report to show that CYP27B1 metabolizes 25,26D(3) to the corresponding 1 alpha-hydroxylated derivative, 1,25,26D(3). It will be interesting to examine the physiological relevance of this finding.