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

Zabul P, Wozniak M, Slominski AT, Preis K, Gorska M, Korozan M, Wieruszewski J, Zmijewski MA, Zabul E, Tuckey R, Kuban-Jankowska A, Mickiewicz W, Knap N - Int J Mol Sci (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics & Gynecology, the Sw. Wojciech Specialist Hospital, Independent Public Complex of Integrated Health Care Units in Gdansk, 50 Al. Jana Pawła II St., Gdansk 80-462, Poland. piotrzabul@wp.pl.

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.

No MeSH data available.


Related in: MedlinePlus

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.
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ijms-16-13043-f003: 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.

Mentions: To test the effect of a natural lipid peroxide on progesterone production, increasing concentrations of AA(OOH) were added to placental mitochondria (Figure 3). This resulted in the inhibition of progesterone synthesis from cholesterol but no effect on its synthesis from pregnenolone. This result indicates that P450scc required to convert cholesterol to pregnenolone, and not 3β-hydroxysteroid dehydrogenase required to convert pregnenolone to progesterone, is the locus of action of the AA(OOH). To determine whether the decrease in P450scc activity was associated with a decrease in P450scc levels, the concentration of functional P450, assessed from its ability to bind CO, was measured following treatment of mitochondria with 100 µM AA(OOH). The cytochrome P450 concentration decreased in a time-dependent manner which was inversely proportional to the increase in the concentration of lipid peroxidation products MDA and HNE (Figure 4). This indicates that inactivation/degradation of P450scc occurs in response to AA(OOH) treatment, possibly as a result of heme breakdown [32,39,40,41,42,43,44].


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

Zabul P, Wozniak M, Slominski AT, Preis K, Gorska M, Korozan M, Wieruszewski J, Zmijewski MA, Zabul E, Tuckey R, Kuban-Jankowska A, Mickiewicz W, Knap N - Int J Mol Sci (2015)

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.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490485&req=5

ijms-16-13043-f003: 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.
Mentions: To test the effect of a natural lipid peroxide on progesterone production, increasing concentrations of AA(OOH) were added to placental mitochondria (Figure 3). This resulted in the inhibition of progesterone synthesis from cholesterol but no effect on its synthesis from pregnenolone. This result indicates that P450scc required to convert cholesterol to pregnenolone, and not 3β-hydroxysteroid dehydrogenase required to convert pregnenolone to progesterone, is the locus of action of the AA(OOH). To determine whether the decrease in P450scc activity was associated with a decrease in P450scc levels, the concentration of functional P450, assessed from its ability to bind CO, was measured following treatment of mitochondria with 100 µM AA(OOH). The cytochrome P450 concentration decreased in a time-dependent manner which was inversely proportional to the increase in the concentration of lipid peroxidation products MDA and HNE (Figure 4). This indicates that inactivation/degradation of P450scc occurs in response to AA(OOH) treatment, possibly as a result of heme breakdown [32,39,40,41,42,43,44].

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics & Gynecology, the Sw. Wojciech Specialist Hospital, Independent Public Complex of Integrated Health Care Units in Gdansk, 50 Al. Jana Pawła II St., Gdansk 80-462, Poland. piotrzabul@wp.pl.

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.

No MeSH data available.


Related in: MedlinePlus