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Medical Hypotheses (2004) 63, 1054–1056 Up-regulatory impact of boron on vitaminD function – does it reflect inhibitionof 24-hydroxylase? Dusan Miljkovica, Natasha Miljkovicb, Mark F. McCartya,* a FutureCeuticals Inc., 5080 Shoreham Plaza, San Diego, CA 92122, USA b Department of Orthopedic Medicine, University of Novi Sad, Novi Sad, Yugoslavia Received 10 December 2003; accepted 13 December 2003 Nutritional intakes of boron have been shown to lessen the adverse consequences of vitamin D deficiency in rodents. Pilot clinical studies suggest that this effect may be mediated, in whole or in part, by an increase in serum25-hydroxyvitamin D. We propose that, in concentrations achievable with good diets, boron suppresses the activity ofthe microsomal enzyme 24-hydroxylase, chiefly responsible for catabolism of this steroid. This inhibition may reflect adirect interaction with the enzyme, or perhaps boron’s ability to form a covalent complex with the product of itsactivity, 24,25-dihydroxyvitamin D. An up-regulatory impact of boron on 25-hydroxyvitamin D is potentially beneficialin light of the fact that the vitamin D status of many individuals is poor during winter months, and traditionalsupplemental doses of this vitamin are often too low to correct this problem. There is growing evidence that goodvitamin D status – as reflected by 25-hydroxyvitamin D levels – may reduce risk for a host of prominent disorders; thus,boron may have the ability to potentiate this protection. Clinical studies also suggest that nutritional boron can up-regulate 17b-estradiol levels in women, including postmenopausal women receiving hormone replacement therapy.
The catabolism of this hormone is achieved by microsomal enzymes catalyzing vicinal hydroxylations – a descriptionthat also applies to 24-hydroxylase. This suggests the more general hypothesis that nutritional boron can inhibit a rangeof microsomal enzymes which insert hydroxyl groups vicinal to existing hydroxyls in steroids – including the enzymeswhich catabolize estradiol and 25-hydroxyvitamin D.
c2004 Elsevier Ltd. All rights reserved.
rats and chickens [1–8]. A clinical study conducted by Nielsen and colleagues [9] may shed some lighton this intriguing phenomemon. 15 volunteers –primarily middle-aged men and women – were Daily intakes of boron comparable to those sup- placed on a low-boron diet (0.23 mg B/2000 kcal) plied by boron-rich natural diets have been shown that was also marginal in magnesium and copper to ameliorate the effects of vitamin D deficiency in status for 63 days. They then continued to consumethis diet for an additional 49 days while beingsupplemented with boron (3 mg daily as sodium * Corresponding author. Present address: NutriGuard Re- borate). Serum levels of 25-hydroxyvitamin D (25- search, 1051 Hermes Ave, Encinitas, CA 92024, USA. Tel.: +1- OH-D), the best marker for vitamin D status, were E-mail address: (M.F. McCarty).
found to average 44.9 nM after the 63 days of boron 0306-9877/$ - see front matter c2004 Elsevier Ltd. All rights reserved.
Up-regulatory impact of boron on vitamin D function deprivation, and 62.4 nM after the 49 days of boron itive inhibitor of the 24-hydroxylase reaction, or, repletion; thus, 25-OH-D rose significantly by about alternatively, perhaps could act to down-regulate 39% when poor boron nutrition was corrected. The expression of this enzyme. Another possibility is 3 mg daily boron dose chosen for repletion is within that boron is a direct inhibitor of the enzyme at the range of boron intakes encountered in varied very modest concentrations; indeed, boron can inhibit numerous enzymes, albeit usually in supra- Is this phenomenon contingent on correction of physiological concentrations [7]. It should be rea- overt boron deficiency? Possibly not. In a recent sonably straightforward to test this hypothesis in open pilot study, 25-OH-D levels were studied vitro using hepatocytes or other cells expressing during boron supplementation in 13 middle-aged 24-hydroxylase activity. Clinically, the testable subjects pre-determined to be vitamin D deficient implication of this hypothesis is that boron sup- (serum 25-OH-D <12 ng/ml) [10]. During 60 days of plementation should increase serum 25-OH-D, supplementation with boron (6 mg daily in the form while serum levels of 24,25-dihydroxyvitamin D of calcium fructoborate, an organic complex that remain constant or decline. (On the other hand, occurs naturally in fruit), 25-OH-D rose significantly the latter compound should concurrently increase by an average of 20%. This change was not likely to if the influence of boron is exerted at the level of reflect a seasonal fluctuation, since the supple- mentation commenced in October and was con-cluded by January (in Serbia); if anything, onewould expect vitamin D status to worsen during thistime. On the other hand, since the subjects were pre-selected for poor vitamin D status, it is con-ceivable that regression to the mean contributed to Assuming that improved boron nutrition can indeed the observed increase in 25-OH-D; evidently, a up-regulate 25-OH-D, why should this be of prac- double-blind design will be required to achieve a tical significance? Granting the growing evidence conclusive confirmation of this effect. Nonethe- that good vitamin D status may reduce risk for a less, these findings are consistent with the possi- range of common pathologies [11,12], it would bility that supplemental boron, administered in seem logical to improve this status simply by high-nutritional doses, can boost 25-OH-D status supplementing with increased amounts of vitamin D even in subjects who are not notably boron – particularly in winter months when ultraviolet exposure is minimal. The problem with this argu-ment is that, for some time to come, most nutri-tionists will be hesitant to recommend doses ofvitamin D sufficiently high to replicate the benefit of ample ultraviolet exposure. The physiological capacity for daily production of cholecalciferol viaultraviolet exposure is about 10,000 IU [13], Assuming that this is a genuine effect, how does whereas most authorities currently recommend boron increase 25-OH-D levels? Since it seems supplemental intakes in the range of 400–800 IU (10–20 mcg). Although Vieth [13] has demonstrated endogenous synthesis of cholecalciferol – a non- that a daily supplemental intake of cholecalciferol enzymatic dermal reaction in which 7-dehydro- of 4000 IU, administered to women during the Ca- nadian winter, is safe and raises serum 25-OH-D synthesis, is cleaved by ultraviolet light and then about halfway to the levels typically observed in undergoes a spontaneous rearrangement – it lifeguards [14], the current misimpression that 2000 seems likely that boron is either up-regulating the IU is the upper safe limit for vitamin D supplemen- 25-hydroxylation step, or suppressing the major tation is likely to discourage the use of optimally pathway of 25-OH-D catabolism, 24-hydroxylation.
effective supplemental intakes of this vitamin for We would like to hypothesize that boron is acting some time to come. Thus, given that vitamin D status is suboptimal for many people during sub- Boron readily forms covalent complexes with stantial portions of the year – even if they use cis-vicinal dihydroxy compounds. Thus, it is con- standard vitamin supplements [15,16] – the pos- ceivable that it can form such a complex with tulated ability of supplemental boron to up-regu- 24,25-dihydroxyvitamin D, the end product of the late 25-OH-D levels (or otherwise act to boost the reaction of 25-OH-D with 24-hydroxylase. This efficacy of suboptimal vitamin D stores) could be of postulated complex might either act as a compet- Although healthful natural diets rich in fruits, substrate utilization and mineral metabolism in the chick.
vegetables, and legumes can provide up to about 10 mg boron daily, surveys show that many people [5] Hunt CD. The biochemical effects of physiologic amounts of dietary boron in animal nutrition models. Environ Health obtain no more than 1 mg boron from their habitual Perspect 1994;102(Suppl. 7):35–43.
diets [17] – high in refined grains, sugars, oils, and [6] Dupre JN, Keenan MJ, Hegsted M, Brudevold AM. Effects of animal products. Daily intakes of boron up to 20 mg dietary boron in rats fed a vitamin D-deficient diet. Environ are considered completely safe. Thus, there is Health Perspect 1994;102(Suppl. 7):55–8.
considerable scope for appropriate nutritional [7] Hunt CD. Biochemical effects of physiological amounts of dietary boron. J Trace Elem Exp Med 1997;9:185–213.
supplementation to improve the boron status of [8] Kurtoglu V, Kurtoglu F, Coskun B. Effects of boron the public. The capacity of such supplementation supplementation of adequate and inadequate vitamin to modulate vitamin D metabolism and activity D3-containing diet on performance and serum biochem- evidently requires further clinical evaluation.
ical characters of broiler chickens. Res Vet Sci 2001;71:183–7.
[9] Nielsen FH, Mullen LM, Gallegher SK. Effect of boron depletion and repletion on blood indicators of calcium status in humans fed a magnesium-low diet. J Trace Elem [10] Miljkovic N. Vitamin D/steroid homeostasis and calcium fructoborate supplementation, 2002 (unpublished manu- Vitamin D is not the only bioactive steroid whose metabolism appears to be influenced by nutritional [11] Holick MF. Vitamin D: A millenium perspective. J Cell intakes of boron – several reports indicate that [12] Zittermann A. Vitamin D in preventive medicine: are we 17b-estradiol concentrations increase when boron ignoring the evidence? Br J Nutr 2003;89:552–72.
in supplemented [18–21]. Notably, this effect is [13] Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D seen in post-menopausal women receiving hormone concentrations, and safety. Am J Clin Nutr 1999;69: replacement therapy – suggesting that a reduction in estradiol catabolism (rather than synthesis) is [14] Vieth R, Chan PC, MacFarlane GD. Efficacy and safety of vitamin D3 intake exceeding the lowest observed adverse responsible. The major routes of estradiol catabo- effect level. Am J Clin Nutr 2001;73:288–94.
lism each involve introduction of a vicinal hydroxyl [15] Vieth R, Cole DE, Hawker GA, Trang HM, Rubin LA.
group – hydroxylations at the 2,4, or 16 position of Wintertime vitamin D insufficiency is common in young 17b-estradiol, which is hydroxylated at the 3 and 17 Canadian women, and their vitamin D intake does not positions. This raises the interesting possibility that prevent it. Eur J Clin Nutr 2001;55:1091–7.
[16] Lehtonen-Veromaa M, Mottonen T, Nuotio I, Irjala K, Viikari boron may be a potent inhibitor for a range of mi- J. The effect of conventional vitamin D(2) supplementation crosomal enzymes which catalyze the insertion of on serum 25 (OH)D concentration is weak among peripu- hydroxyl groups vicinal to existing hydroxyl groups bertal Finnish girls: a 3-y prospective study. Eur J Clin Nutr in steroids – specific examples being 24-hydroxy- lase and the estradiol hydroxylases.
[17] Nielsen FH. The justification for providing dietary guidance for the nutritional intake of boron. Biol Trace Elem Res1998;66:319–30.
[18] Nielsen FH, Hunt CD, Mullen LM, Hunt JR. Effect of dietary boron on mineral, estrogen, and testosteronemetabolism [1] Hunt CD, Herbel JL. Boron affects energy metabolism in the streptozotocin-injected, vitamin D3-deprived rat. Magnes [19] Nielsen FH. Biochemical and physiologic consequences of boron deprivation in humans. Environ Health Perspect [2] Hunt CD, Herbel JL. Effects of dietary boron on calcium and mineral metabolism in the streptozotocin-injected, vitamin [20] Naghii MR, Samman S. The effect of boron supplementation D3-deprived rat. Magnes Trace Elem 1991;10:387–408.
on its urinary excretion and selected cardiovascular risk [3] Hegsted M, Keenan MJ, Siver F, Wozniak P. Effect of boron factors in healthy male subjects. Biol Trace Elem Res on vitamin D deficient rats. Biol Trace Elem Res [21] Samman S, Naghii MR, Lyons Wall PM, Verus AP. The [4] Hunt CD, Herbel JL, Idso JP. Dietary boron modifies the nutritional and metabolic effects of boron in humans and effects of vitamin D3 nutrition on indices of energy animals. Biol Trace Elem Res 1998;66:227–35.


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