Chemical Synthesis of Side-Chain-Hydroxylated Vitamin D3 Derivatives and Their Metabolism by CYP27B1

Abstract

1α,25-Dihydroxyvitamin D₃ (abbreviated here as 1,25D₃ ) is a hormonally active form of vitamin D₃ (D₃ ), and is produced from D₃ by CYP27 A1-mediated hydroxylation at C25, followed by CYP27B1-mediated hydroxylation at C1. Further hydroxylation of 25D₃ and 1,25D₃ occurs at C23, C24 and C26 to generate corresponding metabolites, except for 1,25R,26D₃ . Since the capability of CYP27B1 to hydroxylate C1 of side-chain-hydroxylated metabolites other than 23S,25D₃ and 24R,25D₃ has not been examined, we have here explored the role of CYP27B1 in the C1 hydroxylation of a series of side-chain-hydroxylated D₃ derivatives. We found that CYP27B1 hydroxylates the R diastereomers of 24,25D₃ and 25,26D₃ more effectively than the S diastereomers, but shows almost no activity towards either diastereomer of 23,25D₃ . This is the first report to show that CYP27B1 metabolizes 25,26D₃ to the corresponding 1α-hydroxylated derivative, 1,25,26D₃ . It will be interesting to examine the physiological relevance of this finding.

Keywords: 23,25-dihydroxyvitamin D3; 24,25-dihydroxyvitamin D3; 25,26-dihydroxyvitamin D3; CYP27B1; vitamin D3 metabolites.