Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 278, Issue 39, Pages 38084-38093Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M307028200
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- NHLBI NIH HHS [P01 HL020948, HL20948] Funding Source: Medline
- NIGMS NIH HHS [GM08014] Funding Source: Medline
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The conversion of vitamin D into an active ligand for the vitamin D receptor requires 25-hydroxylation in the liver and 1alpha-hydroxylation in the kidney. Mitochondrial and microsomal vitamin D 25-hydroxylase enzymes catalyze the first reaction. The mitochondrial activity is associated with sterol 27-hydroxylase, a cytochrome P450 (CYP27A1); however, the identity of the microsomal enzyme has remained elusive. A cDNA library prepared from hepatic mRNA of sterol 27-hydroxylase-deficient mice was screened with a ligand activation assay to identify an evolutionarily conserved microsomal cytochrome P450 (CYP2R1) with vitamin D 25-hydroxylase activity. Expression of CYP2R1 in cells led to the transcriptional activation of the vitamin D receptor when either vitamin D-2 or D-3 was added to the medium. Thin layer chromatography and radioimmunoassays indicated that the secosteroid product of CYP2R1 was 25-hydroxyvitamin D-3. Co-expression of CYP2R1 with vitamin D 1alpha-hydroxylase (CYP27B1) elicited additive activation of vitamin D-3, whereas co-expression with vitamin D 24-hydroxylase (CYP24A1) caused inactivation. CYP2R1 mRNA is abundant in the liver and testis, and present at lower levels in other tissues. The data suggest that CYP2R1 is a strong candidate for the microsomal vitamin D 25-hydroxylase.
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