Effects of valproate on xenobiotic biotransformation in rat liver

Rogiers, Vera; Callaerts, A.; Vercruysse, Antoine; Akrawi, M.; Shephard, Elizabeth A.; Phillips, I.

doi:10.1007/bf01962703

Cited by 13 publications

(9 citation statements)

References 21 publications

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“…VPA reduces plasma GSH level by inhibition of GSH synthesis and glutathione disulfide (GSSG) reduction [48], and the acceleration of GSH degradation. VPA also inhibits GSH peroxidase [47] and GSH-S-transferase [52]. Thus, VPA damages GSH system critically.…”

Section: Suggested Explanation Of the Teratogenicity Of Vpa By The Almentioning

confidence: 98%

VPA-induced neural tube defects in mice. I. altered metabolism of sulfur amino acids and glutathione

Hishida

Nau

1998

Teratog. Carcinog. Mutagen.

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Section: Suggested Explanation Of the Teratogenicity Of Vpa By The Almentioning

confidence: 98%

VPA-induced neural tube defects in mice. I. altered metabolism of sulfur amino acids and glutathione

Hishida

Nau

1998

Teratog. Carcinog. Mutagen.

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“…In addition, VPA and TSA are known to be metabolized by cytochrome P450 (CYP) biotransformation enzymes and can increase and/or decrease their activities and/or expression, thereby affecting mechanisms that control drug disposition (Fisher et al ., 1991; Rogiers et al ., 1992, 1995; Isojärvi et al ., 2001; Wen et al ., 2001; Bort et al ., 2004; Cerveny et al ., 2007; Nelson-DeGrave et al ., 2004; Hooven et al ., 2005; Snykers et al ., 2007; Kiang et al ., 2006). Because several CYP enzymes metabolizing a variety of drugs (CYP1A1, 1B1 and 3A4) were found to be expressed in neuroblastoma cells (Poljaková et al ., 2009), here we also investigated whether their expression is influenced by VPA and TSA in these cells.…”

Section: Introductionmentioning

confidence: 99%

Histone deacetylase inhibitors valproate and trichostatin A are toxic to neuroblastoma cells and modulate cytochrome P450 1A1, 1B1 and 3A4 expression in these cells

Hřebačková

Poljaková²,

Eckschlager³

et al. 2009

Interdisciplinary Toxicology

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Histone deacetylase inhibitors such as valproic acid (VPA) and trichostatin A (TSA) were shown to exert antitumor activity. Here, the toxicity of both drugs to human neuroblastoma cell lines was investigated using MTT test, and IC50 values for both compounds were determined. Another target of this work was to evaluate the effects of both drugs on expression of cytochrome P450 (CYP) 1A1, 1B1 and 3A4 enzymes, which are known to be expressed in neuroblastoma cells. A malignant subset of neuroblastoma cells, so-called N-type cells (UKF-NB-3 cells) and the more benign S-type neuroblastoma cells (UKF-NB-4 and SK-N-AS cell lines) were studied from both two points of view. VPA and TSA inhibited the growth of neuroblastoma cells in a dose-dependent manner. The IC50 values ranging from 1.0 to 2.8 mM and from 69.8 to 129.4 nM were found for VPA and TSA, respectively. Of the neuroblastoma tested here, the N-type UKF-NB-3 cell line was the most sensitive to both drugs. The different effects of VPA and TSA were found on expression of CYP1A1, 1B1 and 3A4 enzymes in individual neuroblastoma cells tested in the study. Protein expression of all these CYP enzymes in the S-type SK-N-AS cell line was not influenced by either of studied drugs. On the contrary, in another S-type cell line, UKF-NB-4, VPA and TSA induced expression of CYP1A1, depressed levels of CYP1B1 and had no effect on expression levels of CYP3A4 enzyme. In the N-type UKF-NB-3 cell line, the expression of CYP1A1 was strongly induced, while that of CYP1B1 depressed by VPA and TSA. VPA also induced the expression of CYP3A4 in this neuroblastoma cell line.

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“…It was found that prolonged exposure of rats to VPA results in the self-inducing metabolism of the agent (Fisher et al, 1991). Moreover, Rogiers et al (1992Rogiers et al ( , 1995 have found VPA to be a potent inducer of genes of the rat Cyp2b subfamily, in particular, Cyp2b1 and Cyp2b2. Recently, Eyel et al (2006) have found out that VPA does not affect expression of rat Cyp3a2, an ortholog of human CYP3A4, whereas valpromide, the primary amide of VPA that reveals no HDAC-inhibitory activity, was shown to induce this gene by a nonspecific mechanism.…”

mentioning

confidence: 99%

Valproic Acid Induces CYP3A4 and MDR1 Gene Expression by Activation of Constitutive Androstane Receptor and Pregnane X Receptor Pathways

Červený¹,

Svecova²,

et al. 2007

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ABSTRACT:In our study, we tested the hypothesis whether valproic acid (VPA) in therapeutic concentrations has potential to affect expression of CYP3A4 and MDR1 via constitutive androstane receptor (CAR) and pregnane X receptor (PXR) pathways. Interaction of VPA with CAR and PXR nuclear receptors was studied using luciferase reporter assays, real-time reverse transcriptase polymerase chain reaction (RT-PCR), electrophoretic mobility shift assay (EMSA), and analysis of CYP3A4 catalytic activity. Using transient transfection reporter assays in HepG2 cells, VPA was recognized to activate CYP3A4 promoter via CAR and PXR pathways. By contrast, a significant effect of VPA on MDR1 promoter activation was observed only in CAR-cotransfected HepG2 cells. These data well correlated with up-regulation of CYP3A4 and MDR1 mRNAs analyzed by real-time RT-PCR in cells transfected with expression vectors encoding CAR or PXR and treated with VPA. In addition, VPA significantly up-regulated CYP3A4 mRNA in primary hepatocytes and augmented the effect of rifampicin. EMSA experiments showed VPA-mediated augmentation of CAR/retinoid X receptor ␣ heterodimer binding to direct repeat 3 (DR3) and DR4 responsive elements of CYP3A4 and MDR1 genes, respectively. Finally, analysis of specific CYP3A4 catalytic activity revealed its significant increase in VPA-treated LS174T cells transfected with PXR. In conclusion, we provide novel insight into the mechanism by which VPA affects gene expression of CYP3A4 and MDR1 genes. Our results demonstrate that VPA has potential to up-regulate CYP3A4 and MDR1 through direct activation of CAR and/or PXR pathways. Furthermore, we suggest that VPA synergistically augments the effect of rifampicin in transactivation of CYP3A4 in primary human hepatocytes.

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Effects of valproate on xenobiotic biotransformation in rat liver

Cited by 13 publications

References 21 publications

VPA-induced neural tube defects in mice. I. altered metabolism of sulfur amino acids and glutathione

VPA-induced neural tube defects in mice. I. altered metabolism of sulfur amino acids and glutathione

Histone deacetylase inhibitors valproate and trichostatin A are toxic to neuroblastoma cells and modulate cytochrome P450 1A1, 1B1 and 3A4 expression in these cells

Valproic Acid Induces CYP3A4 and MDR1 Gene Expression by Activation of Constitutive Androstane Receptor and Pregnane X Receptor Pathways

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