Proton gradient-dependent transport of valproic acid in human placental brush-border membrane vesicles

H. Nakamura, F. Ushigome, N. Koyabu, S. Satoh, K. Tsukimori, H. Nakano, Hisakazu Ohtani, Y. Sawada

研究成果: Article

21 引用 (Scopus)

抄録

Purpose. To investigate the transport mechanism of valproic acid across the human placenta, we used human placental brush-border membrane vesicles and compared them with that of lactic acid. Methods. Transport of [3H]valproic acid and [14C]lactic acid was measured by using human placental brush-border membrane vesicles. Results. The uptakes of [3H]valproic acid and [14C]lactic acid into brush-border membrane vesicles were greatly stimulated at acidic extravesicular pH. The uptakes of [3H]valproic acid and [14C]lactic acid were inhibited by various fatty acids, p-chloromercuribenzene sulfonate, α-cyano-4-hydroxycinnamate, and FCCP. A kinetic analysis showed that it was saturable, with Michaelis constants (Kt) of 1.04 ± 0.41 mM and 1.71 ± 0.33 mM for [3H]valproic acid and [14C]lactic acid, respectively. Furthermore, lactic acid competitively inhibited [3H]valproic acid uptake and vice versa. Conclusion. These results suggest that the transport of valproic acid across the microvillous membrane of human placenta is mediated by a proton-linked transport system that also transports lactic acid. However, some inhibitors differentially inhibited the uptakes of [3H]valproic acid and [14C]lactic acid, suggesting that other transport systems may also contribute to the elevated fetal blood concentration of valproic acid in gravida.

元の言語English
ページ(範囲)154-161
ページ数8
ジャーナルPharmaceutical Research
19
発行部数2
DOI
出版物ステータスPublished - 2002
外部発表Yes

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Valproic Acid
Brushes
Microvilli
Protons
Lactic Acid
Membranes
Placenta
Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone
Fetal Blood
Blood
Fatty Acids
Kinetics

ASJC Scopus subject areas

  • Chemistry(all)
  • Pharmaceutical Science
  • Pharmacology

これを引用

Nakamura, H., Ushigome, F., Koyabu, N., Satoh, S., Tsukimori, K., Nakano, H., ... Sawada, Y. (2002). Proton gradient-dependent transport of valproic acid in human placental brush-border membrane vesicles. Pharmaceutical Research, 19(2), 154-161. https://doi.org/10.1023/A:1014242931475

Proton gradient-dependent transport of valproic acid in human placental brush-border membrane vesicles. / Nakamura, H.; Ushigome, F.; Koyabu, N.; Satoh, S.; Tsukimori, K.; Nakano, H.; Ohtani, Hisakazu; Sawada, Y.

:: Pharmaceutical Research, 巻 19, 番号 2, 2002, p. 154-161.

研究成果: Article

Nakamura, H, Ushigome, F, Koyabu, N, Satoh, S, Tsukimori, K, Nakano, H, Ohtani, H & Sawada, Y 2002, 'Proton gradient-dependent transport of valproic acid in human placental brush-border membrane vesicles', Pharmaceutical Research, 巻. 19, 番号 2, pp. 154-161. https://doi.org/10.1023/A:1014242931475
Nakamura, H. ; Ushigome, F. ; Koyabu, N. ; Satoh, S. ; Tsukimori, K. ; Nakano, H. ; Ohtani, Hisakazu ; Sawada, Y. / Proton gradient-dependent transport of valproic acid in human placental brush-border membrane vesicles. :: Pharmaceutical Research. 2002 ; 巻 19, 番号 2. pp. 154-161.
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T1 - Proton gradient-dependent transport of valproic acid in human placental brush-border membrane vesicles

AU - Nakamura, H.

AU - Ushigome, F.

AU - Koyabu, N.

AU - Satoh, S.

AU - Tsukimori, K.

AU - Nakano, H.

AU - Ohtani, Hisakazu

AU - Sawada, Y.

PY - 2002

Y1 - 2002

N2 - Purpose. To investigate the transport mechanism of valproic acid across the human placenta, we used human placental brush-border membrane vesicles and compared them with that of lactic acid. Methods. Transport of [3H]valproic acid and [14C]lactic acid was measured by using human placental brush-border membrane vesicles. Results. The uptakes of [3H]valproic acid and [14C]lactic acid into brush-border membrane vesicles were greatly stimulated at acidic extravesicular pH. The uptakes of [3H]valproic acid and [14C]lactic acid were inhibited by various fatty acids, p-chloromercuribenzene sulfonate, α-cyano-4-hydroxycinnamate, and FCCP. A kinetic analysis showed that it was saturable, with Michaelis constants (Kt) of 1.04 ± 0.41 mM and 1.71 ± 0.33 mM for [3H]valproic acid and [14C]lactic acid, respectively. Furthermore, lactic acid competitively inhibited [3H]valproic acid uptake and vice versa. Conclusion. These results suggest that the transport of valproic acid across the microvillous membrane of human placenta is mediated by a proton-linked transport system that also transports lactic acid. However, some inhibitors differentially inhibited the uptakes of [3H]valproic acid and [14C]lactic acid, suggesting that other transport systems may also contribute to the elevated fetal blood concentration of valproic acid in gravida.

AB - Purpose. To investigate the transport mechanism of valproic acid across the human placenta, we used human placental brush-border membrane vesicles and compared them with that of lactic acid. Methods. Transport of [3H]valproic acid and [14C]lactic acid was measured by using human placental brush-border membrane vesicles. Results. The uptakes of [3H]valproic acid and [14C]lactic acid into brush-border membrane vesicles were greatly stimulated at acidic extravesicular pH. The uptakes of [3H]valproic acid and [14C]lactic acid were inhibited by various fatty acids, p-chloromercuribenzene sulfonate, α-cyano-4-hydroxycinnamate, and FCCP. A kinetic analysis showed that it was saturable, with Michaelis constants (Kt) of 1.04 ± 0.41 mM and 1.71 ± 0.33 mM for [3H]valproic acid and [14C]lactic acid, respectively. Furthermore, lactic acid competitively inhibited [3H]valproic acid uptake and vice versa. Conclusion. These results suggest that the transport of valproic acid across the microvillous membrane of human placenta is mediated by a proton-linked transport system that also transports lactic acid. However, some inhibitors differentially inhibited the uptakes of [3H]valproic acid and [14C]lactic acid, suggesting that other transport systems may also contribute to the elevated fetal blood concentration of valproic acid in gravida.

KW - Human placenta

KW - Lactic acid

KW - Transport mechanism

KW - Valproic acid

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