Valproic Acid Downregulates RBP4 and Elicits Hypervitaminosis A-Teratogenesis—A Kinetic Analysis on Retinol/Retinoic Acid Homeostatic System

Chao-Ming Chuang,Chiung-Chi Peng,Chi-Huang Chang,Hui-Er Wang,Chiu-Lan Hsieh,Kuan-Chou Chen,Robert Y Peng,Vladimir N Uversky

doi:10.1371/journal.pone.0043692

Abstract

BackgroundValproic acid (VPA) is an antiepileptic and anti-migraine prophylactic drug. VPA exhibits two severe side effects, namely acute liver toxicity and teratogenicity. These side effects are usually seen at the genetic and somatic levels. The cited action mechanisms involve inhibition of histone deacetylase, hypofolatenemia, hyperhomocysteinemia, and reactive oxidative stress. The proteomic information associated with VPA teratogenicity is still unavailable. We hypothesized that proteomic analysis might help us identify functional proteins that could be relevantly affected by VPA, and this phenomenon could be very sensitive in early embryonic stage, resulting in VPA teratogenicity.Methodology/Principal FindingsProteomic analysis on the chicken embryos at Hamburger and Hamilton (HH) stage 28 showed that there were significant downregulations of ovotransferrins, carbonic anhydrase-2, retinol binding protein-4 (RBP4), NADH cytochrome b5 reductase 2 (CYB5R2), apolipoprotein A1, and protein SET, together with upregulation of 60S ribosomal protein L22. Among these, RBP4 was the most significantly downregulated (−32%). Kinetic analysis suggested that this situation could trigger hypervitaminosis A (+39.3%), a condition that has been well known to induce teratogenesis..Conclusions/SignificanceThis is the first report showing that VPA dowregulates RBP4. Our finding not only has led to a possible mechanism of VPA teratogenesis, but also has initiated new preventive strategies for avoiding VPA teratogeneis.

Highlights

Valproic acid (VPA, 2-propylpentanoic acid) is an antiepileptic and anti-migraine prophylactic drug
histone deacetylase (HDAC) activity was downregulated by 54.5%, while superoxide dismutase (SOD) activity was downregulated by 21.1%
The production of hydrogen peroxide was significantly increased by 28.3% (Table 1)

Summary

Introduction

Valproic acid (VPA, 2-propylpentanoic acid) is an antiepileptic and anti-migraine prophylactic drug. VPA has anticonvulsive activity via inhibition of the citric acid cycle and elevation of caminobutyric acid (GABA) levels in central nervous system (CNS) [1,2]. Chronic administration of VPA in therapeutic doses to dogs produces intracerebrally approximately 0.5–2.0 mM of 2-n-propylpent-2-enoic acid (D2,3 VPE) (a metabolite of VPA) (Fig. 1) [4]. Valproic acid (VPA) is an antiepileptic and anti-migraine prophylactic drug. VPA exhibits two severe side effects, namely acute liver toxicity and teratogenicity. These side effects are usually seen at the genetic and somatic levels. We hypothesized that proteomic analysis might help us identify functional proteins that could be relevantly affected by VPA, and this phenomenon could be very sensitive in early embryonic stage, resulting in VPA teratogenicity

Methods

Results

Conclusion