Document Detail

Uptake mechanism of valproic acid in human placental choriocarcinoma cell line (BeWo).
MedLine Citation:
PMID:  11334847     Owner:  NLM     Status:  MEDLINE    
Valproic acid is an anticonvulsant widely used for the treatment of epilepsy. However, valproic acid is known to show fetal toxicity, including teratogenicity. In the present study, to elucidate the mechanisms of valproic acid transport across the blood-placental barrier, we carried out transcellular transport and uptake experiments with human placental choriocarcinoma epithelial cells (BeWo cells) in culture. The permeability coefficient of [3H]valproic acid in BeWo cells for the apical-to-basolateral flux was greater than that for the opposite flux, suggesting a higher unidirectional transport in the fetal direction. The uptake of [3H]valproic acid from the apical side was temperature-dependent and enhanced under acidic pH. In the presence of 50 microM carbonyl cyanide p-trifluoromethoxylhydrazone, the uptake of [3H]valproic acid was significantly reduced. A metabolic inhibitor, 10 mM sodium azide, also significantly reduced the uptake of [3H]valproic acid. Therefore, valproic acid is actively transported in a pH-dependent manner on the brush-border membrane of BeWo cells. Kinetic analysis of valproic acid uptake revealed the involvement of a non-saturable component and a saturable component. The Michaelis constant for the saturable transport (K(t)) was smaller under acidic pH, suggesting a proton-linked active transport mechanism for valproic acid in BeWo cells. In the inhibitory experiments, some short-chain fatty acids, such as acetic acid, lactic acid, propanoic acid and butyric acid, and medium-chain fatty acids, such as hexanoic acid and octanoic acid, inhibited the uptake of [3H]valproic acid. The uptake of [3H]valproic acid was also significantly decreased in the presence of 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, salicylic acid and furosemide, which are well-known inhibitors of the anion exchange system. Moreover, p-aminohippuric acid significantly reduced the uptake of [3H]valproic acid. These results suggest that an active transport mechanism for valproic acid exists on the brush-border membrane of placental trophoblast cells and operates in a proton-linked manner.
F Ushigome; H Takanaga; H Matsuo; K Tsukimori; H Nakano; H Ohtani; Y Sawada
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  European journal of pharmacology     Volume:  417     ISSN:  0014-2999     ISO Abbreviation:  Eur. J. Pharmacol.     Publication Date:  2001 Apr 
Date Detail:
Created Date:  2001-05-03     Completed Date:  2001-07-19     Revised Date:  2004-11-17    
Medline Journal Info:
Nlm Unique ID:  1254354     Medline TA:  Eur J Pharmacol     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  169-76     Citation Subset:  IM    
Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
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MeSH Terms
3-O-Methylglucose / metabolism
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / pharmacology
Alanine / metabolism
Anticonvulsants / metabolism
Biological Transport / drug effects
Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / pharmacology
Cell Polarity
Choriocarcinoma / metabolism*,  pathology
Epithelial Cells / metabolism,  pathology
Fatty Acids / pharmacology
Furosemide / pharmacology
Hydrogen-Ion Concentration
Placenta / metabolism*,  pathology
Placental Circulation
Salicylic Acid / pharmacology
Sodium Azide / pharmacology
Teratogens / metabolism
Tumor Cells, Cultured
Uncoupling Agents / pharmacology
Uterine Neoplasms / metabolism*,  pathology
Valproic Acid / metabolism*
p-Aminohippuric Acid / pharmacology
Reg. No./Substance:
0/Anticonvulsants; 0/Fatty Acids; 0/Teratogens; 0/Uncoupling Agents; 146-72-5/3-O-Methylglucose; 26628-22-8/Sodium Azide; 370-86-5/Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; 53005-05-3/4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; 54-31-9/Furosemide; 56-41-7/Alanine; 61-78-9/p-Aminohippuric Acid; 69-72-7/Salicylic Acid; 99-66-1/Valproic Acid

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