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

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

研究成果: Article同行評審

19 引文 斯高帕斯(Scopus)

摘要

Background: 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. 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 Findings: Proteomic 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/Significance: This 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.

原文English
文章編號e43692
期刊PLoS ONE
7
發行號9
DOIs
出版狀態Published - 2012 九月 19

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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