Vitamin D beyond blood: Tissue distribution of vitamin D metabolites after supplementation
Life Sciences 10 August 2024 https://doi.org/10.1016/j.lfs.2024.122942 PDF behind paywall
Highlights
- Vitamin D3 and its key metabolites mediate a variety of important autocrine and paracrine mechanisms.
- These non-endocrine functions highlight the importance of vitamin D3 tissue stores.
- Data on human tissue distribution of vitamin D3 metabolites is lacking, particularly in the context of pregnancy.
- Within the examined dosage ranges, both human and animal studies indicate that vitamin D3 and its metabolites are retained in a dose-dependent manner that is tissue-specific.
- The blood-tissue kinetics and dynamics of vitamin D metabolites after supplementation should be further investigated to inform supplementation strategies.
Vitamin D3's role in mineral homeostasis through its endocrine function, associated with the main circulating metabolite 25-hydroxyvitamin D3, is well characterized. However, the increasing recognition of vitamin D3's paracrine and autocrine functions—such as cell growth, immune function, and hormone regulation—necessitates examining vitamin D3 levels across different tissues post-supplementation. Hence, this review explores the biodistribution of vitamin D3 in blood and key tissues following oral supplementation in humans and animal models, highlighting the biologically active metabolite, 1,25-dihydroxyvitamin D3, and the primary clearance metabolite, 24,25-dihydroxyvitamin D3. While our findings indicate significant progress in understanding how circulating metabolite levels respond to supplementation, comprehensive insight into their tissue concentrations remains limited. The gap is particularly significant during pregnancy, a period of drastically increased vitamin D3 needs and metabolic alterations, where data remains sparse. Within the examined dosage ranges, both human and animal studies indicate that vitamin D3 and its metabolites are retained in tissues selectively.
Notably, vitamin D3 concentrations in tissues show greater variability in response to administered doses. In contrast, its metabolites maintain a more consistent concentration range, albeit different among tissues, reflecting their tighter regulatory mechanisms following supplementation. These observations suggest that serum 25-hydroxyvitamin D3 levels may not adequately reflect vitamin D3 and its metabolite concentrations in different tissues. Therefore, future research should aim to generate robust human data on the tissue distribution of vitamin D3 and its principal metabolites post-supplementation. Relating this data to clinically appropriate exposure metrics will enhance our understanding of vitamin D3's cellular effects and guide refinement of clinical trial methodologies.
Introduction
Vitamin D3 (VD), with its pleiotropic functional profile, plays an indispensable role in the regulation of bone mineral and immune homeostasis, and is deeply embedded in various physiological systems within the human body [1]. VD deficiency, a serum 25-hydroxyvitamin D (25VD) below 20 ng/ml as defined by the Institute of Medicine (IOM) based on skeletal health outcomes, is prevalent globally [[[2], [3], [4], [[5]]. The prevalence of low VD status may be significantly higher when considering the Endocrine Society's definition of deficiency, which is a serum 25VD level of <30 ng/ml [6]. Despite the ubiquitous nature of VD deficiency, its health implications remain subject to debate. Numerous epidemiological studies have shown strong associations of VD deficiency with not only musculoskeletal health outcomes, but also a broad spectrum of adverse health outcomes, such as cancer, respiratory, neuro-developmental, auto-immune, cardiovascular and metabolic diseases [7]. On the other hand, randomized clinical trials (RCTs) examining the effect of oral VD supplementation on these health outcomes have generally been negative. This discrepancy has led some to question VD's role as a causal factor in non-skeletal health outcomes, implying association or even reverse-causality rather than a direct effect. However, the results of these RCT may have been inherently biased towards null findings. This bias can be attributed to the fact that the therapeutic-inspired research design and methodology of most trials failed to meet two critical requirements of nutritional intervention studies [8]. First, trials included large numbers of non-deficient subjects, diluting the potential to observe a true effect. Second, the one-size-fits-all (generic) approach to supplementation failed to ensure that all VD-deficient individuals achieved nutritional sufficiency [8]. When the intervention does not address a deficiency or fails to correct it adequately, evaluating the efficacy of the supplementation becomes impractical. This underscores a critical need for personalized supplementation regimens and reevaluation and novel insights into what constitutes VD sufficiency, extending beyond mere bone health [9].
In recent years, novel approaches have been explored to redefine VD sufficiency. For example, the free hormone hypothesis stipulates that it is primarily unbound VD metabolites that enter cells to exert their effect [10]. Certain physiological and clinical conditions might alter the balance between total and free 25VD, suggesting that measuring the free fraction might improve assessments of VD status [11]. Moreover, 25VD might be increasingly considered a great biomarker of exposure, but not necessarily of effect. Therefore, there has been a growing clinical interest in metabolites bearing closer proximity to VD's physiological actions, such as 1,25-dihydroxyvitamin D (1,25VD), the main biologically active metabolite, and 24,25(OH)2D (24,25VD), the main clearance metabolite. Finally, VD metabolite ratios (VMR) might be useful for accurately evaluating supplementation efficacy [12].
Refining supplementation efficacy necessitates not only a sense of the factors influencing supplementation response, such as body mass index (BMI) or interindividual variability in VD metabolism, but also a deep understanding of its distribution and subsequent target tissue concentrations required for an optimal physiological state [13]. As current guidelines are established based primarily on bone health, different health outcomes may benefit from varying thresholds [6]. More importantly, current research focusses almost exclusively on serum or plasma concentrations of VD and its metabolites, which does not fully capture the extent of tissue penetration post-supplementation. This oversight is significant because unlike drug trials that target specific serum concentrations to ensure immediate and systemic therapeutic efficacy, nutritional trials should aim for a more sustainable change in nutrient availability within the tissues and organs where its primary effects are exerted. Bridging this gap requires a profound understanding of how the body absorbs, distributes, and metabolizes the nutrient after circulatory exposure to establish a link between blood and tissue levels in both the general population and specific sub-populations, such as pregnant women. While extensive pharmacokinetic (PK) assessment is a pillar of the drug developmental process, it remains poorly characterized in the case of VD [14,15]. Therefore, the aim of this review is to elucidate the distribution of VD and its major metabolites in blood and tissue in response to oral VD supplementation. This knowledge is crucial in refining future trial designs and allows for more evidence-based evaluation of VD's efficacy in different body compartments.
Section snippets
Metabolism of vitamin D
Sunlight exposure (UVB) initiates the synthesis of VD in the skin and evolutionarily was the primary source of VD. However, most of the world's populations spend 95 % of their time indoors, and even those who venture outside may use sunscreen, which could decrease exposure to UVB radiation. While dietary intake can modestly support VD reserves, few foods are fortified to a great extent. In contrast, structured oral supplementation leads to significantly increased VD levels (D2 and D3) compared …
1,25-Dihydroxyvitamin D's endocrine, paracrine, and autocrine effects
The endocrine action of the active metabolite, 1,25VD, has been well-characterized in contributing to the maintenance of serum calcium and phosphate homeostasis through the regulation of intestinal and renal (re)absorption. Recent research has shifted focus towards 1,25VD's autocrine and/or paracrine activities within tissues as potentially important for non-skeletal related effects. While the endocrine effects of 1,25VD are linked to the serum levels of 25VD, its autocrine and paracrine …
Vitamin D's biodistribution in blood
The bioavailability of oral VD supplements exhibits significant inter-individual variability, with estimated rates between 55 and 99 % [39]. Factors influencing VD absorption, and hence its bioavailability, include gastric and intestinal conditions (pH, gut enzymes and microbiome), other host-associated factors (baseline levels, age, morbidities and genetic variation [40]), and the supplement formulation (e.g., tablets, solutions, gels) [41,42]. Notably, VD absorption is not limited to passive …
Distribution of vitamin D and its metabolites across tissues following supplementation (radioactive tracking)
The 1972 study by Mawer et al. on the uptake of intravenously administered 14C-labelled VD in human tissues is foundational in elucidating the quantitative distribution and storage of VD following exogenous administration [65]. Analyzing data from seven patients, Mawer et al. discovered a consistent pattern of rapid serum clearance of total radioactivity, followed by its redistribution to various tissues. Notably, the liver, kidneys, lungs, and spleen accumulated a minimal portion, <2 % of the…
Vitamin D metabolite response during pregnancy (1,25 VD can double)
Pregnancy presents a unique physiological state during which VD metabolism is significantly altered with a surge in its concentrations, indicating an extensive physiological requirement for this hormone. During pregnancy, the conversion rate of VD to 25VD remains comparable to those in the non-pregnant state [120]. However, feedback regulation of 1,25VD becomes uncoupled, leading to a progressive increase in concentrations of 100–150 % upon conception and into the second trimester. This upward…
Discussion
Previous investigations have extensively characterized the changes to human serum 25VD after prolonged oral VD supplementation, identifying several individual-level modifiers of this response. Additionally, supplementation has been shown to increase serum 1,25VD in both pregnant and non-pregnant individuals, although significant increases in the latter are primarily observed during VD deficiency. Based on the summarized data from the reviewed studies (Table 1), it is evident that there's a…
Conclusions and future perspective
The current work provides insights into the distribution of VD and key metabolites throughout the body of various species. These findings have the potential to enhance research on the impact of VD supplementation, which may ultimately contribute to the development of more precise and effective supplementation guidelines as well as refined metrics for clinical studies. Future experimental research must rigorously investigate the serum and tissue levels of 1,25VD and 24,25VD in both humans and…
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