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

Research output: Contribution to journalArticle

15 Citations (Scopus)

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. 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.

Original languageEnglish
Article numbere43692
JournalPLoS ONE
Volume7
Issue number9
DOIs
Publication statusPublished - 2012 Sep 19

Fingerprint

Hypervitaminosis A
valproic acid
hypervitaminosis A
Teratogenesis
Retinol-Binding Proteins
retinol-binding protein
retinoic acid
Valproic Acid
Tretinoin
Vitamin A
vitamin A
Down-Regulation
kinetics
Kinetics
teratogenicity
Proteomics
proteomics
Cytochrome-B(5) Reductase
Cellular Retinol-Binding Proteins
Conalbumin

All Science Journal Classification (ASJC) codes

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

Cite this

Chuang, Chao Ming ; Chang, Chi Huang ; Wang, Hui Er ; Chen, Kuan Chou ; Peng, Chiung Chi ; Hsieh, Chiu-Lan ; Peng, Robert Y. / Valproic Acid Downregulates RBP4 and Elicits Hypervitaminosis A-Teratogenesis-A Kinetic Analysis on Retinol/Retinoic Acid Homeostatic System. In: PLoS ONE. 2012 ; Vol. 7, No. 9.
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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. 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.",
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Valproic Acid Downregulates RBP4 and Elicits Hypervitaminosis A-Teratogenesis-A Kinetic Analysis on Retinol/Retinoic Acid Homeostatic System. / Chuang, Chao Ming; Chang, Chi Huang; Wang, Hui Er; Chen, Kuan Chou; Peng, Chiung Chi; Hsieh, Chiu-Lan; Peng, Robert Y.

In: PLoS ONE, Vol. 7, No. 9, e43692, 19.09.2012.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Valproic Acid Downregulates RBP4 and Elicits Hypervitaminosis A-Teratogenesis-A Kinetic Analysis on Retinol/Retinoic Acid Homeostatic System

AU - Chuang, Chao Ming

AU - Chang, Chi Huang

AU - Wang, Hui Er

AU - Chen, Kuan Chou

AU - Peng, Chiung Chi

AU - Hsieh, Chiu-Lan

AU - Peng, Robert Y.

PY - 2012/9/19

Y1 - 2012/9/19

N2 - 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.

AB - 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.

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