title: Valproic acid downregulates RBP4 and elicits hypervitaminosis A-teratogenesis--a kinetic analysis on retinol/retinoic acid homeostatic system.
abstract: 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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Department of Nursing, Hungkuang University, Shalu County, Taichung City, Taiwan.
authors.forename: Chao-Ming
authors.initials: CM
authors.lastname: Chuang
authors.forename: Chi-Huang
authors.initials: CH
authors.lastname: Chang
authors.forename: Hui-Er
authors.initials: HE
authors.lastname: Wang
authors.forename: Kuan-Chou
authors.initials: KC
authors.lastname: Chen
authors.forename: Chiung-Chi
authors.initials: CC
authors.lastname: Peng
authors.forename: Chiu-Lan
authors.initials: CL
authors.lastname: Hsieh
authors.forename: Robert Y
authors.initials: RY
authors.lastname: Peng
mesh_terms: D000014:Abnormalities, Drug-Induced; D000818:Animals; D002642:Chick Embryo; D047108:Embryonic Development / Q000187:drug effects / Q000235:genetics; D006655:Histone Deacetylases / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics; D006861:Hydrogen Peroxide / Q000378:metabolism; D006986:Hypervitaminosis A / Q000235:genetics* / Q000378:metabolism; D007700:Kinetics; D010641:Phenotype; D040901:Proteomics; D054839:Retinol-Binding Proteins, Plasma / Q000235:genetics* / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D013723:Teratogens / Q000378:metabolism* / Q000633:toxicity; D014635:Valproic Acid / Q000494:pharmacology* / Q000633:toxicity; D014801:Vitamin A / Q000378:metabolism* / Q000633:toxicity
chemical_list: D054839:Retinol-Binding Proteins, Plasma; D013723:Teratogens; D014801:Vitamin A; D014635:Valproic Acid; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; D006655:Histone Deacetylases