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Hypothesis: Vitamin D Binding Protein limits vitamin D benefits outside of kidney too– Oct 2013

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Vitamin D and DBP: The free hormone hypothesis revisited.

J Steroid Biochem Mol Biol. 2013 Oct 3. pii: S0960-0760(13)00186-6. doi:0.1016/j.jsbmb.2013.09.012.
Chun RF, Peercy BE, Orwoll ES, Nielson CM, Adams JS, Hewison M.
Orthopaedic Hospital Research Center, University of California Los Angeles, Los Angeles, CA 90095, USA.

The last five years have witnessed a remarkable renaissance in vitamin D research and a complete re-evaluation of its benefits to human health. Two key factors have catalyzed these changes.
First, it now seems likely that localized, tissue-specific, conversion of 25-hydroxyvitamin D (25OHD) to 1,25-dihydroxyvitamin D (1,25(OH)2D) drives many of the newly recognized effects of vitamin D on human health.
The second key factor concerns the ongoing discussion as to what constitutes adequate or optimal serum vitamin D (25OHD) status, with the possibility that vitamin D-deficiency is common to communities across the globe.
These two concepts appear to be directly linked when low serum concentrations of 25OHD compromise intracrine generation of 1,25(OH)2D within target tissues.

But, is this an over-simplification? Pro-hormone 25OHD is a lipophilic molecule that is transported in the circulation bound primarily to vitamin D binding protein (DBP).

While the association between 25OHD and DBP is pivotal for renal handling of 25OHD and endocrine synthesis of 1,25(OH)2D, what is the role of DBP for extra-renal synthesis of 1,25(OH)2D?
We hypothesize that binding to DBP impairs delivery of 25OHD to the vitamin D-activating enzyme 1α-hydroxylase in some target cells.

Specifically, it is unbound, 'free' 25OHD that drives many of the non-classical actions of vitamin D. Levels of free' 25OHD are dependent on the concentration of DBP and alternative serum binding proteins such as albumin, but will also be influenced by variations in DBP binding affinity for specific vitamin D metabolites.

The aim of this review will be to discuss the merits of free 25OHD' as an alternative marker of vitamin D status, particularly in the context of non-classical responses to vitamin D.

Copyright © 2013. Published by Elsevier Ltd.
PMID: 24095930

Horm Res Paediatr. 2013;79:162-8. doi: 10.1159/000348847. Epub 2013 Mar 20.
Santos BR, Mascarenhas LP, Boguszewski MC, Spritzer PM.
Gynecologic Endocrinology Unit, Division of Endocrinology, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.

BACKGROUND/AIMS:Vitamin D deficiency has been recognized as a worldwide epidemic affecting several pediatric and adolescent populations. We determined the genotype and haplotype distribution of the rs4588 and rs7041 polymorphisms of the GC gene encoding vitamin D-binding protein (DBP) and investigated the associations between these gene variants and their haplotypes with 25-hydroxyvitamin D [25(OH)D] levels in girls from South Brazil.

METHODS:Cross-sectional study including 198 apparently healthy girls aged 10-18 years. Plasma levels of 25(OH)D were assessed by radioimmunoassay.
Participants were genotyped for rs4588 and rs7041 by real-time PCR, with allelic discrimination assays.

RESULTS:Mean chronological age and BMI percentile were 13.17 ± 1.74 years and 57.81 ± 29.03, respectively. Sufficient circulating 25(OH)D levels (≥30 ng/ml) were found in 9.1% of the overall group, insufficient levels (20-29.9 ng/ml) in 59.6%, and deficient levels (<20 ng/ml) in 31.3%. The AA genotype of rs4588, TT genotype of rs7041 and CT-AT/AT-AT (GC 1f-2/2-2) diplotypes were significantly associated with lower 25(OH)D levels, even after adjustment for age and season at the time of blood collection.

CONCLUSIONS:The GC gene genotype may be related to the susceptibility to low 25(OH)D levels in female children and adolescents.

Copyright © 2013 S. Karger AG, Basel.
PMID: 23548751

See also VitaminDWiki