title: Inhibition of choline uptake in syncytial microvillus membrane vesicles of human term placenta. Specificity and nature of interaction.
abstract: The potency and nature of the inhibitory effect of various cationic drugs on the transport of choline across the placental syncytial microvillus membrane was investigated. Tetraethylammonium, a model substrate for organic cation transport, was a poor inhibitor. Enlarging the degree of alkylation of the quaternary ammonium increased the inhibitory effect, in proportion with increasing lipophilicity. Log concentration vs % control uptake curves showed marked differences in inhibitory potency for the different cationic drugs. Hemicholinium-3 inhibited mediated choline uptake in the micromolar range, whereas atropine and mepiperphenidol were less potent. The H2-receptor antagonists cimetidine, ranitidine, and famotidine inhibited choline uptake in the millimolar ranges. Dixon analysis revealed a competitive nature of inhibition for hemicholinium-3 and atropine (Ki = 40 microM and 1.2 mM, respectively). Cimetidine interacted noncompetitively (Ki = 3.4 mM). Since relatively high concentrations were needed to reach half maximal inhibition, impairment of fetal choline supply due to maternal drug use during pregnancy is not to be expected.
authors.affiliation: Department of Pharmacology, Faculty of Medical Sciences, University of Nijmegen, The Netherlands.
authors.forename: E M
authors.initials: EM
authors.lastname: Van der Aa
authors.forename: A C
authors.initials: AC
authors.lastname: Wouterse
authors.forename: J H
authors.initials: JH
authors.lastname: Copius Peereboom-Stegeman
authors.forename: F G
authors.initials: FG
authors.lastname: Russel
mesh_terms: D001285:Atropine / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002794:Choline / Q000378:metabolism*; D018680:Cholinergic Antagonists / Q000494:pharmacology; D002927:Cimetidine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015738:Famotidine / Q000494:pharmacology; D005260:Female; D006426:Hemicholinium 3 / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008431:Maternal-Fetal Exchange; D026901:Membrane Transport Proteins; D008871:Microvilli / Q000378:metabolism; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011899:Ranitidine / Q000494:pharmacology; D013757:Tetraethylammonium Compounds / Q000494:pharmacology; D014327:Trophoblasts / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D018680:Cholinergic Antagonists; D006635:Histamine H2 Antagonists; D026901:Membrane Transport Proteins; D014179:Neurotransmitter Uptake Inhibitors; D013757:Tetraethylammonium Compounds; C065637:choline transporter; D006426:Hemicholinium 3; D015738:Famotidine; D001285:Atropine; D002927:Cimetidine; D011899:Ranitidine; D002794:Choline