Ethanol inhibits functional activity of the human intestinal dipeptide transporter hPepT1 expressed in Xenopus oocytes.
BACKGROUND
The pathological effects of high alcohol (ethanol) consumption on gastrointestinal and hepatic systems are well recognized. However, the effects of ethanol intake on gastric and intestinal absorption and transport systems remain unclear. The present study investigates the effects of ethanol on the human peptide transporter 1 (hPepT1) which mediates the transport of di-and tripeptides as well as several orally administered peptidomimetic drugs such as beta-lactam antibiotics (e.g., penicillin), angiotensin-converting enzyme inhibitors, the anti-neoplastic agent bestatin, and prodrugs of acyclovir.


METHODS
Xenopus oocytes were injected with hPepT1 cRNA and incubated for 3 to 10 days. Currents induced by glycyl-sarcosine (Gly-Sar), Ala-Ala (dipeptides), penicillin and enalapril measured in the presence or absence of ethanol were determined using an 8-channel 2-electrode voltage clamp system, with a membrane potential of -70 mV and 11 voltage steps of 100 milliseconds (from +50 mV to -150 mV in -20 mV increments).


RESULTS
Ethanol (200 mM) inhibited Gly-Sar and Ala-Ala currents by 42 and 30%, respectively, with IC(50)s of 184 and 371 mM, respectively. Ethanol reduced maximal transport capacity (I(max)) of hPepT1 for Gly-Sar without affecting Gly-Sar binding affinity (K(0.5) and Hill coefficient). Penicillin- and enalapril-induced currents were significantly less than those induced by dipeptides and were not inhibited by ethanol.


CONCLUSIONS
Ethanol significantly reduced transport of dipeptides via a reduction in transport capacity, rather than competing for binding sites in hPepT1. Ethanol inhibition or alteration of transport function may be a primary causative factor contributing to both the nutritional deficits as well as the immunological deficiencies that many alcoholics experience including alcohol liver disease and brain damage.
Li
Kaixun
K
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California 90033, USA. Kaixunli@usc.edu
Xu
Liya
L
Kulkarni
Ashutosh A
AA
Perkins
Daya I
DI
Haworth
Ian S
IS
Davies
Daryl L
DL
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000493:pharmacokinetics; D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics; D004151:Dipeptides / Q000378:metabolism; D004594:Electrophysiology; D004656:Enalapril / Q000493:pharmacokinetics; D000431:Ethanol / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007421:Intestine, Small / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D010406:Penicillins / Q000493:pharmacokinetics; D000074011:Peptide Transporter 1; D051381:Rats; D027981:Symporters / Q000037:antagonists & inhibitors*; D014981:Xenopus
D000806:Angiotensin-Converting Enzyme Inhibitors; D000900:Anti-Bacterial Agents; D004151:Dipeptides; D010406:Penicillins; D000074011:Peptide Transporter 1; C082186:SLC15A1 protein, human; D027981:Symporters; C002956:alanylalanine; D000431:Ethanol; D004656:Enalapril