Valproic acid transport in the choriocarcinoma placenta cell line JEG-3 proceeds independently of the proton-dependent transporters MCT1 and MCT4

• Published in: Drug metabolism and pharmacokinetics 2018-12, Vol.33 (6), p.270-274
• Main Authors: Ishiguro, Yuri, Furugen, Ayako, Narumi, Katsuya, Nishimura, Ayako, Hirano, Takeshi, Kobayashi, Masaki, Iseki, Ken
• Format: Article
• Language: English
• Subjects: Antiepileptic drug; Biological Transport; Cell Line, Tumor; Humans; Hydrogen-Ion Concentration; JEG-3; Monocarboxylate transporter; Monocarboxylic Acid Transporters - antagonists & inhibitors; Monocarboxylic Acid Transporters - genetics; Monocarboxylic Acid Transporters - metabolism; Muscle Proteins - antagonists & inhibitors; Muscle Proteins - genetics; Muscle Proteins - metabolism; Placenta; Protons; RNA, Small Interfering - pharmacology; Symporters - antagonists & inhibitors; Symporters - genetics; Symporters - metabolism; Valproic acid; Valproic Acid - antagonists & inhibitors; Valproic Acid - metabolism
• ISSN: 1347-4367; 1880-0920
• DOI: 10.1016/j.dmpk.2018.03.004

Medication therapy is the first line of treatment in the management of epilepsy. Fetal exposure to valproic acid (VPA), an antiepileptic drug, poses an elevated risk of teratogenicity in early pregnancy. Some studies have reported that monocarboxylate transporters (MCTs) may be involved in the placental transport of VPA. However, it has not been determined which MCTs contribute to VPA transport into the placenta. Therefore, the aim of this study was to determine how MCTs contribute to VPA transport into the placenta using the human placenta choriocarcinoma cell line JEG-3. VPA uptake was investigated using JEG-3 cells and radiolabeled VPA. MCT expression in JEG-3 cells was detected using RT-PCR and western blotting. Knockdown of MCTs was carried out using siRNAs. VPA uptake into JEG-3 cells was pH- and concentration-dependent, and described by using the Michaelis–Menten equation (Km = 0.95 ± 0.17 mM; Vmax = 19.3 ± 1.21 nmol/mg protein/15 s). MCT1 and MCT4 expression was found in JEG-3 cells, and typical MCT inhibitors significantly inhibited VPA uptake into JEG-3 cells. However, knockdown of MCT1 and MCT4 did not alter VPA uptake. In conclusion, VPA transport is mediated by a proton-dependent transporter in JEG-3 cells, but not by MCT1 and MCT4. [Display omitted]