Rat cytochrome P450C24 (CYP24) does not metabolize 1,25-dihydroxyvitamin D2to calcitroic acid

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Abstract
1α‐Hydroxy‐23 carboxy‐24,25,26,27‐tetranorvitamin D3 (calcitroic acid) is known to be the major water‐soluble metabolite produced during the deactivation of 1,25‐(OH)2D3. This deactivation process is carried out exclusively by the multicatalytic enzyme CYP24 and involves a series of oxidation reactions at C24 and C23 leading to side‐chain cleavage and, ultimately, formation of the calcitroic acid. Like 1,25‐(OH)2D3, 1α,25‐1,25‐(OH)2D2 is also known to undergo side‐chain oxidation and side‐chain cleavage to form calcitroic acid (Zimmerman et al. [2001]. 1,25‐(OH)2D2 differs from 1,25‐(OH)2D3 by the presence of a double bond at C22 and a methyl group at C24. To date, there have been no studies detailing the participation of CYP24 in the production of calcitroic acid from 1,25‐(OH)2D2. We, therefore, studied the metabolism of 1,25‐(OH)2D3 and 1,25‐(OH)2D2 using a purified rat CYP24 system. Lipid and aqueous‐soluble metabolites were prepared for characterization. Aqueous‐soluble metabolites were subjected to reverse‐phase high‐pressure liquid chromatography (HPLC) analysis. As expected, 1,23(OH)2‐24,25,26,27‐tetranor D and calcitroic acid were the major lipid and aqueous‐soluble metabolites, respectively, when 1,25‐(OH)2D3 was used as substrate. However, when 1,25‐(OH)2D2 was used as substrate, 1,24(R),25‐(OH)3D2 was the major lipid‐soluble metabolite with no evidence for the production of either 1,23(OH)2‐24,25,26,27‐tetranor D or calcitroic acid. Apparently, the CYP24 was able to 24‐hydroxylate 1,25‐(OH)2D2, but was unable to effect further changes, which would result in side‐chain cleavage. These data suggest that the presence of either the double bond at C22 or the C24 methyl group impedes the metabolism of 1,25‐(OH)2D2 to calcitroic acid by CYP24 and that enzymes other than CYP24 are required to effect this process. J. Cell. Biochem. 88: 282–285, 2003. Published 2002 Wiley‐Liss, Inc.