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Antiepileptic drugs alter the expression of placental carriers: An in vitro study in a human placental cell line
Author(s) -
RubinchikStern Miriam,
Shmuel Miri,
Eyal Sara
Publication year - 2015
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.13037
Subject(s) - abcg2 , organic anion transporting polypeptide , lamotrigine , pharmacology , carbamazepine , valproic acid , folate receptor , solute carrier family , transporter , phenytoin , western blot , chemistry , endocrinology , biology , medicine , atp binding cassette transporter , biochemistry , cancer cell , epilepsy , cancer , gene , neuroscience
Summary Objective Antiepileptic drugs ( AED s) affect the expression of carriers for drugs and nutrients at several blood‐tissue barriers, but their impact on placental carriers is largely unknown. Our aim was to study the effects of AED s in human placental cells on the expression of carriers for hormones, nutrients, and drugs: folate placental uptake carriers (reduced folate carrier, RFC ; folate receptor α, FR α) and efflux transporters (breast cancer resistance protein, BCRP and multidrug resistance protein 2) and thyroid hormone uptake transporters ( l ‐type amino acid transporter‐ LAT 1 and organic anion transporting polypeptides‐ OATP s). Methods The human trophoblast BeWo cells were incubated with phenytoin ( PHT ), valproic acid ( VPA ), carbamazepine ( CBZ ), levetiracetam ( LEV ), lamotrigine ( LTG ), or their vehicles at concentrations that mostly represent their therapeutic range. RT ‐ PCR and western blot analysis were utilized to study the effects of AED s on carriers’ mRNA and protein expression, respectively. The activity of BCRP was evaluated by accumulation studies. Results Compared with controls, VPA ‐treated cells displayed half the levels of RFC mRNA and protein (p < 0.05) and up to 2.7‐fold increases in BCRP mRNA and protein expression (p < 0.05), together with enhanced BCRP activity. PHT increased the expression of BCRP and LAT 1 by 2.9‐fold and 2.5‐fold, respectively (p < 0.01). LTG modulated the levels of FR α transcript and protein, whereas LEV altered those of RFC , LAT 1, and OATP s 1A2 and 4A1. CBZ affected carrier expression at the mRNA but not the protein level. All the AED s altered to a modest extent the transcription of nuclear receptors known to regulate transporter expression. Significance These findings suggest a possible effect of AED s on placental transport mechanisms for folate and thyroid hormones as well as those involved in the elimination of potential toxins from the fetus. Identification of AED effects on the placental barrier could be a first step toward a more rational pharmacotherapy and supplemental therapy in pregnant women with epilepsy.