Differential Metabolic Stability of 4α,25- and 4β,25-Dihydroxyvitamin D and Identification of Their Metabolites.

Vitamin D () is metabolized by various cytochrome P450 (CYP) enzymes, resulting in the formation of diverse metabolites. Among them, 4α,25-dihydroxyvitamin D () and 4β,25-dihydroxyvitamin D () are both produced from 25-hydroxyvitamin D () by CYP3A4. However, is detectable in serum, whereas is not.

Synthesis of Deuterium-Labeled Vitamin D Metabolites as Internal Standards for LC-MS Analysis.

Blood levels of the vitamin D (D) metabolites 25-hydroxyvitamin D (25(OH)D), 24,25-dihydroxyvitamin D, and 1α,25-dihydroxyvitamin D (1,25(OH)D) are recognized indicators for the diagnosis of bone metabolism-related diseases, D deficiency-related diseases, and hypercalcemia, and are generally measured by liquid-chromatography tandem mass spectrometry (LC-MS/MS) using an isotope dilution method. However, other D metabolites, such as 20-hydroxyvitamin D and lactone D, also show interesting biological activities and stable isotope-labeled derivatives are required for LC-MS/MS analysis of their concentrations in serum. Here, we describe a versatile synthesis of deuterium-labeled D metabolites using A-ring synthons containing three deuterium atoms.

Synthesis of C2-Alkoxy-Substituted 19-Nor Vitamin D Derivatives: Stereoselectivity and Biological Activity.

The active form of vitamin D (D), 1a,25-dihydroxyvitamn D (1,25D), plays a central role in calcium and bone metabolism. Many structure-activity relationship (SAR) studies of D have been conducted, with the aim of separating the biological activities of 1,25D or reducing its side effects, such as hypercalcemia, and SAR studies have shown that the hypercalcemic activity of C2-substituted derivatives and 19-nor type derivatives is significantly suppressed. In the present paper, we describe the synthesis of 19-nor type 1,25D derivatives with alkoxy groups at C2, by means of the Julia-Kocienski type coupling reaction between a C2 symmetrical A ring ketone and a CD ring synthon.

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

1α,25-Dihydroxyvitamin D (abbreviated here as 1,25D ) is a hormonally active form of vitamin D (D ), and is produced from D by CYP27 A1-mediated hydroxylation at C25, followed by CYP27B1-mediated hydroxylation at C1. Further hydroxylation of 25D and 1,25D occurs at C23, C24 and C26 to generate corresponding metabolites, except for 1,25R,26D . Since the capability of CYP27B1 to hydroxylate C1 of side-chain-hydroxylated metabolites other than 23S,25D and 24R,25D has not been examined, we have here explored the role of CYP27B1 in the C1 hydroxylation of a series of side-chain-hydroxylated D derivatives.