Valproic acid augments vitamin D receptor-mediated induction of CYP24 by vitamin D3: A possible cause of valproic acid-induced osteomalacia?

Vrzal, Radim; Doricakova, Aneta; Novotná, Aneta; Bachleda, Petr; Bitman, Michal; Pávek, Petr; Dvořák, Zdeněk

doi:10.1016/j.toxlet.2010.11.008

Cited by 39 publications

(22 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Some reports also proposed that vitamin D deficiency was significantly frequent in patients taking EIAEDs but still common in those taking non-EIAEDs [44][45][46][47] . On the other hand, VPA, a wide-spectrum AED, is commonly regarded as an inhibitor of cytochrome P450 system, but this belief was recently challenged, as VPA was reported to augment the expressions of CYP24 and CYP3A4 through in vitro experiments [48,49] . Although researches are controversial concerning the influence of VPA on vitamin D, longitudinal studies are more prone to show reduced vitamin D levels in patients taking VPA [17,19,20,50] .…”

Section: Discussionmentioning

confidence: 99%

Effect of Antiepileptic Therapy on Serum 25(OH)D3 and 24,25(OH)2D3 Levels in Epileptic Children

Jiang²,

Zhu³

et al. 2016

Ann Nutr Metab

View full text Add to dashboard Cite

Background: Vitamin D deficiency is not only associated with the adverse effects of chronic treatment with antiepileptic drugs (AEDs), but also with epilepsy. Although emerging evidence suggests that AEDs can accelerate the vitamin D catabolism, resulting in suboptimal vitamin D status, there are a limited number of studies examining the vitamin D status in epileptic patients, especially in first-episode or AEDs-naïve children. Methods: Determined with high-performance liquid chromatography-tandem mass spectrometry, circulating 25(OH)D₃ and 24,25(OH)₂D₃ levels, and 24,25(OH)₂D₃:25(OH)D₃ ratio were compared between AEDs-treated epileptic (n = 363) and control (n = 159) children. To further figure out whether the patients were in a vitamin D deficient prone state even before treatment, epileptic children before their initiation of treatment (n = 51) were enrolled into a follow-up study. Results: A significant decrease of 25(OH)D₃ and 24,25(OH)₂D₃ levels, but a significant increase of 24,25(OH)₂D₃:25(OH)D₃ ratio was observed in epileptic children, compared with controls. Baseline 25(OH)D₃, 24,25(OH)₂D₃ and 24,25(OH)₂D₃:25(OH)D₃ ratio in the follow-up group were similar to those in controls, but significantly changed with 2 months of AED therapy. Conclusions: Disturbed vitamin D levels were possibly the consequence of AED therapy, rather than the contributing factor of epilepsy. Collectively, circulating vitamin D levels should be monitored and corrected in AEDs-treated epileptic children.

show abstract

Section: Discussionmentioning

confidence: 99%

Effect of Antiepileptic Therapy on Serum 25(OH)D3 and 24,25(OH)2D3 Levels in Epileptic Children

Jiang²,

Zhu³

et al. 2016

Ann Nutr Metab

View full text Add to dashboard Cite

show abstract

“…However, it is also well-known that VPA activates different MAP kinases and other signaling pathways, such as GSK3α and β, Akt, the phosphoinositol pathway, and the tricarboxylic acid cycle in different cells 15 . Recently, we found that VPA slightly activated the extracellular signal-regulated kinase (ERK) and weakly inhibited c-Jun N-terminal kinase (JNK), while it had no effect on p38 kinase in HEK293 cells 26 . However, a completely different pattern of MAPKs activation in other cell lines and tissues has been demonstrated in previous research.…”

Section: Discussionmentioning

confidence: 99%

“…In an earlier paper, we demonstrated that VPA activated ERK but not c-Jun-N-terminal kinase (JNK) nor p38 MAPKs in HEK cells 26 . The effect of valproate on MAPKs activation in quiescent non-tumour primary human hepatocytes has however, not been studied.…”

Section: Introductionmentioning

confidence: 95%

Valproate activates ERK signaling pathway in primary human hepatocytes

Bitman¹,

Vrzal²,

Dvořák³

et al. 2014

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

Self Cite

View full text Add to dashboard Cite

Aim. Valproic acid (VPA) is a widely-used anticonvulsant and mood-stabilizing agent. VPA is also known to inhibit histone deacetylases (HDACs) affecting the expression of numerous genes. Methods. In the present study, we examined the effect of VPA on the extracellular signal-related kinase (ERK, p42/p44) pathway (Ras-Raf-MEK-ERK) belonging to the mitogen-activated protein kinases (MAPKs) pathways in primary human hepatocytes. In the liver, the pathway is associated with progression of hepatocellular carcinoma. Results. We found that VPA in a therapeutically relevant concentration (500 μM) activates the ERK pathway, as indicated by increased ERK Thr202/Tyr204 phosphorylation. Interestingly, a prototype HDAC inhibitor, trichostatin A, also activated ERK phosphorylation in primary human hepatocytes. These data suggest that HDAC inhibition might be the primary stimulus for ERK pathway activation in primary human hepatocytes. Notably, U0126, a MEK1 inhibitor, was ineffective in inhibiting ERK pathway activation, likely due to its metabolic deactivation in metabolically competent primary human hepatocytes. Conclusion. We conclude that VPA activates the ERK pathway in primary human hepatocytes.

show abstract

“…Transiently transfected gene reporter cell lines used for assessment of transcription activity pregnane X receptor (PXR) and vitamin D receptor (VDR) were described elsewhere [36].…”

Section: Gene Reporter Assaysmentioning

confidence: 99%

Pleiotropic effects of gold(I) mixed-ligand complexes of 9-deazahypoxanthine on transcriptional activity of receptors for steroid hormones, nuclear receptors and xenoreceptors in human hepatocytes and cell lines

Kubešová

Trávnı́ček

Dvořák

2016

European Journal of Medicinal Chemistry

View full text Add to dashboard Cite

Valproic acid augments vitamin D receptor-mediated induction of CYP24 by vitamin D3: A possible cause of valproic acid-induced osteomalacia?

Cited by 39 publications

References 33 publications

Effect of Antiepileptic Therapy on Serum 25(OH)D<sub>3</sub> and 24,25(OH)<sub>2</sub>D<sub>3</sub> Levels in Epileptic Children

Effect of Antiepileptic Therapy on Serum 25(OH)D<sub>3</sub> and 24,25(OH)<sub>2</sub>D<sub>3</sub> Levels in Epileptic Children

Valproate activates ERK signaling pathway in primary human hepatocytes

Pleiotropic effects of gold(I) mixed-ligand complexes of 9-deazahypoxanthine on transcriptional activity of receptors for steroid hormones, nuclear receptors and xenoreceptors in human hepatocytes and cell lines

Contact Info

Product

Resources

About