Cytochrome P450 enzymes in the bioactivation of vitamin D to its hormonal form (Review)
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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Document Type: Research Article
Affiliations: Division of Biochemistry, Department of Pharmaceutical Biosciences, University of Uppsala, S-751 23 Uppsala, Sweden
Publication date: January 1, 2001
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- The International Journal of Molecular Medicine is a monthly, peer-reviewed journal devoted to the publication of high quality studies related to the molecular mechanisms of human disease. The journal welcomes research on all aspects of molecular and clinical research, ranging from biochemistry to immunology, pathology, genetics, human genomics, microbiology, molecular pathogenesis, molecular cardiology, molecular surgery and molecular psychology.
The International Journal of Molecular Medicine aims to provide an insight for researchers within the community in regard to developing molecular tools and identifying molecular targets for the diagnosis and treatment of a diverse number of human diseases.
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