Inhibition of choline uptake in syncytial microvillus membrane vesicles of human term placenta. Specificity and nature of interaction.
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.
Van der Aa
E M
EM
Department of Pharmacology, Faculty of Medical Sciences, University of Nijmegen, The Netherlands.
Wouterse
A C
AC
Copius Peereboom-Stegeman
J H
JH
Russel
F G
FG
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
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