Cytochrome P450 enzymes in the bioactivation of vitamin D to its hormonal form (Review)

  • Authors:
    • K. Wikvall
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  • Published online on: February 1, 2001     https://doi.org/10.3892/ijmm.7.2.201
  • Pages: 201-209
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Abstract

The formation of 1α,25-dihydroxyvitamin D3 requires a 25-hydroxylation followed by a 1α-hydroxylation catalyzed by cytochrome P450 (CYP) enzymes in liver and kidney. The aim of this review is to give a brief summary of our research on the cytochrome P450 enzymes catalyzing the 25-hydroxylation and 1α-hydroxylation and to discuss the results in relation to other published literature on these enzymes. Two hepatic P450 enzymes catalyzing 25-hydroxylation of vitamin D3 exist in mammalian liver - one mitochondrial and one microsomal. The mitochondrial vitamin D3 25-hydroxylase is apparently identical with CYP27A, an obligatory enzyme in bile acid biosynthesis in liver. The microsomal 25-hydroxylase has been purified to apparent homogeneity from pig liver. The enzyme catalyzed 25-hydroxylation of vitamin D3, 1α-hydroxyvitamin D3, vitamin D2 and 1α-hydroxyvitamin D2. A cDNA encoding pig liver microsomal vitamin D3 25-hydroxylase has been isolated in this laboratory. The primary structure of vitamin D3 25-hydroxylase shows 70-80% identity with members of the CYP2D subfamily and has been designated CYP2D25. Three different 1α-hydroxylating cytochromes P450 in kidney, i.e. CYP27A, CYP27B and a microsomal 1α-hydroxylase, have been described. Mitochondrial cytochrome P450, catalyzing 1α-hydroxylation and 27-hydroxylation but not 24-hydroxylation of 25-hydroxyvitamin D3, was partially purified from pig kidney. Purification and inhibition experiments as well as experiments with a monoclonal antibody against CYP27A indicated that one single enzyme catalyzes both 1α- and 27-hydroxylation. Treatment of rats with a single i.v. dose of 1α,25-dihydroxyvitamin D3 resulted in a marked suppression of CYP27A mRNA levels in kidney. The results suggest a role for CYP27A as a renal mitochondrial 1α-hydroxylase. Subsequently, several research groups reported the isolation of cDNA encoding mouse, rat and human kidney 25-hydroxyvitamin D3 1α-hydroxylase. The amino acid sequences deduced from these cDNA clones were similar but differed from that of CYP27A. This 1α-hydroxylase constitutes a new CYP27 subfamily, CYP27B. The expression of CYP27B was found to be influenced by vitamin D status and parathyroid hormone. Mutations in the CYP27B gene have been identified in patients with pseudovitamin D-deficiency rickets. A microsomal P450 catalyzing 1α-hydroxylation of 25-hydroxyvitamin D3 has been purified to apparent homogeneity from pig kidney. This finding demonstrate the presence of a microsomal 1α-hydroxylase in addition to the mitochondrial 1α-hydroxylases in kidney. The relative importance and regulation of the different renal 1α-hydroxylases in the bioactivation of vitamin D3 under normal and pathological conditions will be subject for future studies.

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February 2001
Volume 7 Issue 2

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Wikvall K: Cytochrome P450 enzymes in the bioactivation of vitamin D to its hormonal form (Review). Int J Mol Med 7: 201-209, 2001
APA
Wikvall, K. (2001). Cytochrome P450 enzymes in the bioactivation of vitamin D to its hormonal form (Review). International Journal of Molecular Medicine, 7, 201-209. https://doi.org/10.3892/ijmm.7.2.201
MLA
Wikvall, K."Cytochrome P450 enzymes in the bioactivation of vitamin D to its hormonal form (Review)". International Journal of Molecular Medicine 7.2 (2001): 201-209.
Chicago
Wikvall, K."Cytochrome P450 enzymes in the bioactivation of vitamin D to its hormonal form (Review)". International Journal of Molecular Medicine 7, no. 2 (2001): 201-209. https://doi.org/10.3892/ijmm.7.2.201