Valproic Acid
Effects of Valproate:
- It is believed to affect the function of the neurotransmitter GABA (as a GABA transaminase inhibitor) in the human brain, making it an alternative to lithium salts in treatment of bipolar disorder.In addition to blocking transamination of GABA, Valproate is believed to reverse the transamination process to form more GABA.
- other mechanisms in neuropsychiatric disorders
- the Wnt/beta-catenin and ERK pathways
- inositol signaling
- arachidonate metabolism
- It blocks the voltage-gated sodium channels and T-type Calcium channels.These mechanisms make Valproic Acid a Broad Spectrum Anticonvulsant drug.
- It is an inhibitor of the enzyme histone deacetylase 1 and jnhibits HIV and cancer proliferation.
Side effects
Thyroid function
Thyroid function in children with epilepsy treated with sodium valproate monotherapy: a prospective study. 2009
Sex Hormones function
Multiple mechanisms induce transcriptional silencing of a subset of genes, including oestrogen receptor alpha, in response to deacetylase inhibition by valproic acid and trichostatin A. 2005
Methionine metabolism
Acute valproate administration impairs methionine metabolism in rats. 2002
Glycine increase
Papers serum aminoacid valproic acid
Ureagenesis
Valproate inhibits ureagenesis and can be toxic to mitochondria. in OMIM
more side effects AIFA dec 2009
Serotonin
Effects of valproate on serotonin-induced intracellular calcium mobilization in human platelets. 2007
HDAC (histone deacetylatase) inhibition
Genet Vaccines Ther. 2007 Sep 24;5:10.
HDAC inhibitor valproic acid upregulates CAR in vitro and in vivo.
Segura-Pacheco B, Avalos B, Rangel E, Velazquez D, Cabrera G.
Vectorology and Gene Therapy Laboratory, National Cancer Institute, Av, San Fernando No 22, Del, Tlalpan, CP 14080, Mexico City, Mexico. g.cabrera@yahoo.com.
ABSTRACT: BACKGROUND: The presence of CAR in diverse tumor types is heterogeneous with implications in tumor transduction efficiency in the context of adenoviral mediated cancer gene therapy. Preliminary studies suggest that CAR transcriptional regulation is modulated through histone acetylation and not through promoter methylation. Furthermore, it has been documented that the pharmacological induction of CAR using histone deacetylase inhibitor (iHDAC) compounds is a viable strategy to enhance adenoviral mediated gene delivery to cancer cells in vitro. The incorporation of HDAC drugs into the overall scheme in adenoviral based cancer gene therapy clinical trials seems rational. However, reports using compounds with iHDAC properties utilized routinely in the clinic are pending. Valproic acid, a short chained fatty acid extensively used in the clinic for the treatment of epilepsy and bipolar disorder has been recently described as an effective HDAC inhibitor at therapeutic concentrations. METHODS: We studied the effect of valproic acid on histone H3 and H4 acetylation, CAR mRNA upregulation was studied using semiquantitative PCR and adenoviral transduction on HeLa cervical cancer cells, on MCF-7 breast cancer cells, on T24 transitional cell carcinoma of the bladder cells. CAR mRNA was studied using semiquantitative PCR on tumor tissue extracted from patients diagnosed with cervical cancer treated with valproic acid. RESULTS: CAR upregulation through HDAC inhibition was observed in the three cancer cell lines with enhancement of adenoviral transduction. CAR upregulation was also observed in tumor samples obtained from patients with cervical cancer treated with therapeutic doses of valproic acid. These results support the addition of the HDAC inhibitor valproic acid to adenoviral mediated cancer gene therapy clinical trials to enhance adenoviral mediated gene delivery to the tumor cells.
Valproate and Collagen
Papers Valproate bone loss
J Proteome Res. 2010 Jul 7. [Epub ahead of print]
Valproate and Bone Loss: iTRAQ Proteomics Show that Valproate Reduces Collagens and Osteonectin in SMA Cells. 2010
Valproate is commonly used as an anticonvulsant and mood stabilizer, but its long-term side-effects can include bone loss. As a histone deacetylase (HDAC) inhibitor, valproate has also been considered for treatment of spinal muscular atrophy (SMA). Using iTRAQ labeling technology, followed by two-dimensional liquid chromatography and mass spectrometry analysis, a quantitative comparison of the proteome of an SMA cell line, with and without valproate treatment, was performed. The most striking change was a reduction in collagens I and VI, while over 1000 other proteins remained unchanged. The collagen I alpha-chain precursor was also reduced by more than 50% suggesting that valproate affects collagen I synthesis. The collagen-binding glycoprotein, osteonectin (SPARC, BM-40) was one of the few other proteins that were significantly reduced by valproate treatment. Collagen I is the main protein component of bone matrix and osteonectin has a major role in bone development, so the results suggest a possible molecular mechanism for bone loss following long-term exposure to valproate. SMA patients may already suffer bone weakness as a result of SMN1 gene deletion, so further bone loss would be undesirable.
Papers PTH Valproate
CAR
Drug Metab Dispos. 2010 Sep;38(9):1493-8. Epub 2010 Jun 1.
Histone deacetylase inhibitors induce cytochrome P450 2B by activating nuclear receptor constitutive androstane receptor., 2010
Takizawa D, Kakizaki S, Horiguchi N, Tojima H, Yamazaki Y, Ichikawa T, Sato K, Mori M.
Source
Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma, Japan.
Abstract
Valproic acid, a histone deacetylase (HDAC) inhibitor, induces the cytochrome P450 2B subfamily. However, the effects of HDAC inhibitors on CYP2B induction are still not fully understood. Nuclear receptor constitutive androstane receptor (CAR) is a key regulator of CYP2B induction. In this study, we investigated the effect of HDAC inhibitors on CAR-mediated CYP2B induction. The expression of CYP2B6 mRNA was induced in HepG2 cells stably expressing mouse CAR (Ym17) by HDAC inhibitors including valproic acid, phenylbutyrate, and trichostatin A. HDAC inhibitors activated the phenobarbital-responsive enhancer module of the CYP2B6 promoter in transient transfection reporter assays with Ym17 cells. Furthermore, HDAC inhibitors synergistically augmented the effect of the CAR ligand, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, in the transactivation of CYP2B6 mRNA and the promoter assay in Ym17 cells. Intraperitoneal injection of HDAC inhibitors induced Cyp2b10 mRNA in wild-type mice. However, such induction was not observed in CAR mice. Immunoprecipitation demonstrated that CAR formed a complex with HDACs. HDAC inhibitors diminished the binding between CAR and HDAC1 and augmented the binding of steroid receptor coactivator-1 (SRC-1) to CAR. Furthermore, small interfering RNA knockdown of HDAC1 increased CYP2B6 mRNA expression. These results provide novel insight into the mechanism by which HDAC inhibitors affect gene expression of CYP2B6. HDAC inhibitors have the potential to up-regulate CYP2B6 through the dissociation of HDAC1 and recruitment of SRC-1 to receptor CAR.
