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, alpha-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.
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, alpha-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.
Authors: P D Prasad; H Wang; R Kekuda; T Fujita; Y J Fei; L D Devoe; F H Leibach; V Ganapathy Journal: J Biol Chem Date: 1998-03-27 Impact factor: 5.157
Authors: Nicole Terbach; Rishita Shah; Rachel Kelemen; Peter S Klein; Dmitri Gordienko; Nigel A Brown; Christopher J Wilkinson; Robin S B Williams Journal: J Cell Sci Date: 2011-06-07 Impact factor: 5.285