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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

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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ijms-16-13043-f006: 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.

Mentions: We proposed a cellular model of preeclampsia exposing JAR trophoblast cells to AA(OOH)-induced lipid peroxidation analogously to our mitochondrial experimental model of preeclampsia which has been discussed above. Biochemical and ultrastructural changes as observed in JAR cell line exposed to oxidative stress phenomena had been previously defined [75,76], and were in accord with the characteristics of preeclamptic placental cells [116]. We observed the same classical products of lipid peroxidation, namely MDA and HNE as we did in the isolated placental mitochondria having been exposed to AA(OOH). Lipid peroxidation was completely inhibited in cell culture pretreated with 50 µM TEMPOL (AA(OOH)+TEMPOL). Interestingly enough, contrary to common enzymatic antioxidants, nitroxides like 4-OH-TEMPO (TEMPOL) can provide protection of biological systems from oxidative stress by pre-emptying of carbon-centered radicals in lipid peroxidation chain reaction [117,118], thus preventing cytochrome P450scc heme destruction, which might be the mechanism of the observed reduction in P450scc activity (Figure 3) and concentration (Figure 4). High protective efficacy of 4-OH-TEMPO in the placental cell culture model (Figure 5 and Figure 6) can be explained by extremely high absolute rate constant for the cross-coupling reaction of several carbon-centered radicals with various nitroxides (2.3 × 109 M−1·s−1) [117,119,120]. As opposed to 4-OH-TEMPO, Vitamin E preferentially scavenges peroxyl radical, and proved to be ineffective in the prevention of preeclampsia [56,121]. The results of this study allow us to propose that alkyl radicals rather than peroxyl radicals are mainly involved in the oxidative damage to trophoblast cells under the conditions of preeclampsia (Figure 6).


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)

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.
© Copyright Policy
Related In: Results  -  Collection

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

ijms-16-13043-f006: 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.
Mentions: We proposed a cellular model of preeclampsia exposing JAR trophoblast cells to AA(OOH)-induced lipid peroxidation analogously to our mitochondrial experimental model of preeclampsia which has been discussed above. Biochemical and ultrastructural changes as observed in JAR cell line exposed to oxidative stress phenomena had been previously defined [75,76], and were in accord with the characteristics of preeclamptic placental cells [116]. We observed the same classical products of lipid peroxidation, namely MDA and HNE as we did in the isolated placental mitochondria having been exposed to AA(OOH). Lipid peroxidation was completely inhibited in cell culture pretreated with 50 µM TEMPOL (AA(OOH)+TEMPOL). Interestingly enough, contrary to common enzymatic antioxidants, nitroxides like 4-OH-TEMPO (TEMPOL) can provide protection of biological systems from oxidative stress by pre-emptying of carbon-centered radicals in lipid peroxidation chain reaction [117,118], thus preventing cytochrome P450scc heme destruction, which might be the mechanism of the observed reduction in P450scc activity (Figure 3) and concentration (Figure 4). High protective efficacy of 4-OH-TEMPO in the placental cell culture model (Figure 5 and Figure 6) can be explained by extremely high absolute rate constant for the cross-coupling reaction of several carbon-centered radicals with various nitroxides (2.3 × 109 M−1·s−1) [117,119,120]. As opposed to 4-OH-TEMPO, Vitamin E preferentially scavenges peroxyl radical, and proved to be ineffective in the prevention of preeclampsia [56,121]. The results of this study allow us to propose that alkyl radicals rather than peroxyl radicals are mainly involved in the oxidative damage to trophoblast cells under the conditions of preeclampsia (Figure 6).

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