Review
Does vitamin D protect against DNA damage?

https://doi.org/10.1016/j.mrfmmm.2012.02.005Get rights and content

Abstract

Vitamin D is a secosteroid best known for its role in maintaining bone and muscle health. Adequate levels of vitamin D may also be beneficial in maintaining DNA integrity. This role of vitamin D can be divided into a primary function that prevents damage from DNA and a secondary function that regulates the growth rate of cells. The potential for vitamin D to reduce oxidative damage to DNA in a human has been suggested by clinical trial where vitamin D supplementation reduced 8-hydroxy-2′-deoxyguanosine, a marker of oxidative damage, in colorectal epithelial crypt cells. Studies in animal models and in different cell types have also shown marked reduction in oxidative stress damage and chromosomal aberrations, prevention of telomere shortening and inhibition of telomerase activity following treatment with vitamin D. The secondary function of vitamin D in preventing DNA damage includes regulation of the poly-ADP-ribose polymerase activity in the DNA damage response pathway involved in the detection of DNA lesions. It is also able to regulate the cell cycle to prevent the propagation of damaged DNA, and to regulate apoptosis to promote cell death. Vitamin D may contribute to prevention of human colorectal cancer, though there is little evidence to suggest that prevention of DNA damage mediates this effect, if real. Very limited human data mean that the intake of vitamin D required to minimise DNA damage remains uncertain.

Introduction

Normal cellular metabolism is supported by mechanisms aimed at detecting and repairing DNA damage, with the primary aim of maintaining genome stability. Certain chemicals, including reactive molecules generated during cellular metabolism, can covalently bind to DNA forming mutagenic adducts, which may lead to nucleotide substitution, formation of abasic sites, or formation of single or double strand breaks. Three common threats to the integrity of DNA are: (i) overactivity of spontaneous reactions (mainly hydrolysis) that are intrinsic to the chemical nature of DNA, (ii) endogenous metabolic reactive oxygen or nitrogen species and lipid peroxidation products, and (iii) damage by exogenous physical and chemical agents, e.g. dimerisation of adjacent cytosine or thymine bases by ambient ultraviolet (UV) exposure [1].

Adequate nutrient levels are essential in maintaining genome stability as deficiency can influence toxin absorption, retention, repair and detoxification pathways [2]. One such nutrient is vitamin D, a seco-steroid known for its role in maintaining bone and muscle health [3]. Vitamin D deficiency is associated with increased frequencies of chromosomal aberrations and sister chromatid exchanges due to oxidative, hypoxic and apoptotic stress [4], [5], [6], [7]. Thus maintaining sufficient vitamin D levels is potentially important in preventing these changes.

Vitamin D is mainly produced in the skin through a process initiated by exposure to solar UVB radiation (290–315 nm); pro-vitamin D3 (7-dehydrocholesterol) in the epidermis and dermis is converted, by photolysis, to pre-vitamin D3. Pre-vitamin D3 isomerises rapidly at body temperature to the more thermodynamically stable vitamin D3, (cholecalciferol) [8], [9], [10]. During this transformation process, vitamin D3 moves from the plasma membrane to the extracellular space, and then enters the dermal capillary bed bound to vitamin-D-binding protein [9]. The bound vitamin D3 migrates in the bloodstream to the liver, where it is hydroxylated to 25-hydroxy vitamin D3 (25-(OH)D) (calcidiol), a stable metabolite with a half-life of several weeks [10]. Calcidiol is further metabolised, mainly in kidneys but also in other tissues, to 1α,25-dihydroxyvitamin D (calcitriol), which is the physiologically active form of vitamin D.

Calcitriol is the biologically active form of vitamin D [10], and exerts its effects via two pathways: the classical genomic pathway which involves interaction with vitamin D receptor (VDR) and the rapid response or the non-genomic pathway [11]. The genomic pathway is involved in a host of cellular processes, including some that protect cells against DNA damage, induce cell cycle arrest and, consequently, inhibit cell proliferation, increase apoptosis and induce differentiation [12], [13]. The rapid response pathway is limited to the cis-form of calcitriol [11], [14], and is involved in minimising UV-induced DNA damage by providing in vivo photo-protection [15] (Fig. 1).

Section snippets

Vitamin D and UV induced DNA damage in skin cells.

Exposure of skin cells to UV increases nitric oxide production, thus increasing reactive oxygen species (ROS). These processes are associated with increased oxidative damage, reduced DNA repair, immune suppression and formation of cyclobutane pyrimidine dimers (CPDs) in DNA [16], [17]. CPDs are the most commonly found DNA photo lesions in skin caused by exposure to UV. Calcitriol treatment has been shown to protect skin cells against these hazardous effects of UVB radiation. Pre-treatment of

Vitamin D and DNA oxidation

ROS result in intermediates that can produce peroxides and free radicals. Failure to detoxify these agents can result in oxidative damage and, at the nuclear level, lead to production of abasic sites, purine or pyrimidine oxidation and DNA strand breaks. High levels of oxidative stress in cells, if unresolved, can lead to diseases such as bone loss and cancer. Low serum vitamin D levels have been associated with a reduction in bone density and an elevation in levels of

Vitamin D, micronuclei and DNA strand breaks

Oxidative damage can induce chromosomal aberrations (CA), abnormalities in chromosomal structure that manifest themselves as acentric chromosome fragments and asymmetrical rearrangements such as dicentric chromosomes [30]. These abnormal chromosomes are not segregated properly during mitosis and may result in formation of nuclear anomalies such as micronuclei and abnormal distribution of nuclear material or chromosome loss leading to aneuploidy [31]. Breakage of DNA strands, followed by a

Vitamin D, telomeres and telomerase

Telomeres are DNA hexamer repeat sequences at the end of the chromosomes, and function together with the telosome protein structure to stop chromosome ends from fusing to each other which would cause serious mitotic and genetic aberrations. Telomeres undergo attrition with each cycle of cell replication and may reach a critically short length that no longer enables the telosome structure at the ends of chromosomes to be properly maintained. This, in turn, leads to telomere end fusions and

Vitamin D and DNA damage response

Mammalian cells are equipped with molecular mechanisms to recruit and activate repair at DNA damage sites, through a signal transduction pathway called the DNA damage response (DDR) [46], [47]. This pathway senses DNA damage and sets in place a response to protect genome integrity and overcome the threat by activating and recruiting genome maintenance factors to sites of DNA damage, and coordinating pathways to employ efficient DNA repair. It is mediated by proteins in the

Vitamin D and regulation of the cell cycle

DNA lesions are detected at checkpoints in the cell cycle to block cell proliferation until the DNA is repaired. If irreparable, an elimination process is activated to remove the damaged cell. These processes prevent damaged DNA from being inherited by daughter cells. If unrepaired prior to replication, DNA damage may lead to the propagation of nucleotide substitution or deletion, or chromosome rearrangement [1].

DNA is replicated in the synthesis phase (S-phase) of the cell cycle. In the

Vitamin D and apoptosis

Apoptosis is programmed cell death, a process of cellular self-destruction aimed at maintaining tissue homeostasis or integrity. It is a defence mechanism against the proliferation of genetically aberrant cells within tissues and organs. For example, the degree of metastatic spread of cancer is dependent on the ability of cancer cells to evade apoptosis [48].

Calcitriol has significant antiproliferative effects in vitro and in vivo (reviewed [48]). Apoptosis is mediated by caspase activation,

Vitamin D and DNA damage in humans

Present evidence that vitamin D prevents DNA damage and regulates the cell cycle is limited to results of studies in cultured cells and experimental animal models. While vitamin D may protect against colorectal cancer [82], and perhaps other cancers, in humans, there is currently no direct evidence that this effect, if real, is mediated by way of protection against DNA damage. Importantly, however, in a placebo controlled trial of calcium 2 g/day, vitamin D3 800 IU/day or both for six months, in

Recommendations for dietary vitamin D to prevent DNA damage

There is no substantial evidence at a population level, to directly link vitamin D to prevention of DNA damage. There is some evidence in humans that insufficient to deficient levels of calcidiol are linked prospectively to diseases that have been associated with increased levels of DNA damage [85], [86], [87], [88], [89]. Specifically, insufficient levels of calcidiol (30–50 nmol/L) have been associated with increased risks of diabetes, cardiovascular disease, hypertension, cancer, and multiple

Funding

National Health and Medical Research Council of Australia project grant number 464895.

Conflict of interest

Bruce K. Armstrong has previously held a research grant of $10,000 from Blackmores Ltd., a nutritional products manufacturer that produces vitamin D supplements.

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