Valproic Acid Downregulates RBP4 and Elicits Hypervitaminosis A-Teratogenesis—A Kinetic Analysis on Retinol/Retinoic Acid Homeostatic System
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 hist...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Public Library of Science
2012
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3446952/ https://www.ncbi.nlm.nih.gov/pubmed/23028466 http://dx.doi.org/10.1371/journal.pone.0043692 |
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author | Chuang, Chao-Ming Chang, Chi-Huang Wang, Hui-Er Chen, Kuan-Chou Peng, Chiung-Chi Hsieh, Chiu-Lan Peng, Robert Y. |
author_facet | Chuang, Chao-Ming Chang, Chi-Huang Wang, Hui-Er Chen, Kuan-Chou Peng, Chiung-Chi Hsieh, Chiu-Lan Peng, Robert Y. |
author_sort | Chuang, Chao-Ming |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3446952 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-34469522012-10-01 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. PLoS One Research Article 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. Public Library of Science 2012-09-19 /pmc/articles/PMC3446952/ /pubmed/23028466 http://dx.doi.org/10.1371/journal.pone.0043692 Text en © 2012 Chuang et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article 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 |
title | Valproic Acid Downregulates RBP4 and Elicits Hypervitaminosis A-Teratogenesis—A Kinetic Analysis on Retinol/Retinoic Acid Homeostatic System |
title_full | Valproic Acid Downregulates RBP4 and Elicits Hypervitaminosis A-Teratogenesis—A Kinetic Analysis on Retinol/Retinoic Acid Homeostatic System |
title_fullStr | Valproic Acid Downregulates RBP4 and Elicits Hypervitaminosis A-Teratogenesis—A Kinetic Analysis on Retinol/Retinoic Acid Homeostatic System |
title_full_unstemmed | Valproic Acid Downregulates RBP4 and Elicits Hypervitaminosis A-Teratogenesis—A Kinetic Analysis on Retinol/Retinoic Acid Homeostatic System |
title_short | Valproic Acid Downregulates RBP4 and Elicits Hypervitaminosis A-Teratogenesis—A Kinetic Analysis on Retinol/Retinoic Acid Homeostatic System |
title_sort | valproic acid downregulates rbp4 and elicits hypervitaminosis a-teratogenesis—a kinetic analysis on retinol/retinoic acid homeostatic system |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3446952/ https://www.ncbi.nlm.nih.gov/pubmed/23028466 http://dx.doi.org/10.1371/journal.pone.0043692 |
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