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Controlled Clinical Trial
. 2015 Jun 9;16(6):13043-64.
doi: 10.3390/ijms160613043.

A Proposed Molecular Mechanism of High-Dose Vitamin D3 Supplementation in Prevention and Treatment of Preeclampsia

Piotr Zabul  1 , Michal Wozniak  2 , Andrzej T Slominski  3 , Krzysztof Preis  4 , Magdalena Gorska  5 , Marek Korozan  6 , Jan Wieruszewski  7 , Michal A Zmijewski  8 , Ewa Zabul  9 , Robert Tuckey  10 , Alicja Kuban-Jankowska  11 , Wieslawa Mickiewicz  12 , Narcyz Knap  13
Affiliations
Controlled Clinical Trial

A Proposed Molecular Mechanism of High-Dose Vitamin D3 Supplementation in Prevention and Treatment of Preeclampsia

Piotr Zabul et al. Int J Mol Sci. .

Abstract

A randomized prospective clinical study performed on a group of 74 pregnant women (43 presenting with severe preeclampsia) proved that urinary levels of 15-F(2t)-isoprostane were significantly higher in preeclamptic patients relative to the control (3.05 vs. 2.00 ng/mg creatinine). Surprisingly enough, plasma levels of 25-hydroxyvitamin D3 in both study groups were below the clinical reference range with no significant difference between the groups. In vitro study performed on isolated placental mitochondria and placental cell line showed that suicidal self-oxidation of cytochrome P450scc may lead to structural disintegration of heme, potentially contributing to enhancement of oxidative stress phenomena in the course of preeclampsia. As placental cytochrome P450scc pleiotropic activity is implicated in the metabolism of free radical mediated arachidonic acid derivatives as well as multiple Vitamin D3 hydroxylations and progesterone synthesis, we propose that Vitamin D3 might act as a competitive inhibitor of placental cytochrome P450scc preventing the production of lipid peroxides or excess progesterone synthesis, both of which may contribute to the etiopathogenesis of preeclampsia. The proposed molecular mechanism is in accord with the preliminary clinical observations on the surprisingly high efficacy of high-dose Vitamin D3 supplementation in prevention and treatment of preeclampsia.

Keywords: arachidonic acid hydroperoxide; isoprostanes; placenta; preeclampsia; vitamin D3.

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Figures

Figure 1
Figure 1
Urinary isoprostane excretion as calculated per mg of creatinine in preeclamptic women vs. control (* p < 0.01).
Figure 2
Figure 2
Vitamin D3 (25(OH)D3) plasma levels in preeclamptic women vs. control. No significant difference between groups was found.
Figure 3
Figure 3
Progesterone biosynthesis as a function of AA(OOH) concentration in placental mitochondria (measured as percentage of substrate conversion). Progesterone biosynthesis from cholesterol or pregnenolone was measured following a 15 min. incubation. Data presented as mean ± SD obtained from five independent experiments.
Figure 4
Figure 4
Cytochrome P450scc level after treatment with arachidonic acid hydroperoxide (AA(OOH)). Lipid peroxidation induced by AA(OOH) was measured from the production of MDA and HNE. Data are presented as mean ± SD obtained from five independent experiments expressed as percentage of control.
Figure 5
Figure 5
Lipid peroxidation in JAR cell culture. Control cells, cells treated with 100 µM Arachidonic Acid Hydroperoxide AA(OOH), cells treated with 100 µM AA(OOH) and 50 µM TEMPOL (AA(OOH) + TEMPOL). Products of lipid peroxidation (MDA plus HNE) were significantly elevated in cells treated with AA(OOH) only. Data presented as mean ± SD obtained from five independent experiments.
Figure 6
Figure 6
A proposed molecular mechanism of high-dose Vitamin D3 supplementation in prevention or treatment of preeclampsia. Vitamin D3 acts as a competitive inhibitor of placental cytochrome P450scc preventing the production of lipid peroxides and excess progesterone, both of which may contribute to the etiopathogenesis of preeclampsia. 4-OH-TEMPO (TEMPOL) protects placental mitochondria as an effective scavenger of carbon-centered radicals.
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