Differential Metabolic Stability of 4α,25- and 4β,25-Dihydroxyvitamin D 3 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 no...

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Bibliographic Details
Published in:Biomolecules (Basel, Switzerland) Switzerland), 2023-06, Vol.13 (7)
Main Authors: Mizumoto, Yuka, Sakamoto, Ryota, Iijima, Kazuto, Nakaya, Naoto, Odagi, Minami, Tera, Masayuki, Hirokawa, Takatsugu, Sakaki, Toshiyuki, Yasuda, Kaori, Nagasawa, Kazuo
Format: Article
Language:English
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Summary: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. We hypothesized that the reason for this is a difference in the susceptibility of and to CYP24A1-mediated metabolism. Here, we synthesized and , and confirmed that has greater metabolic stability than . We also identified 4α,24 ,25- and 4β,24 ,25-trihydroxyvitamin D ( and ) as metabolites of and , respectively, by HPLC comparison with synthesized authentic samples. Docking studies suggest that the β-hydroxy group at C4 contributes to the greater metabolic stability of by blocking a crucial hydrogen-bonding interaction between the C25 hydroxy group and Leu325 of CYP24A1.
ISSN:2218-273X