title: Interaction of beta-lactam antibiotics with histidine residue of rat H+/peptide cotransporters, PEPT1 and PEPT2.
abstract: Peptide transporters mediate the H+-coupled uphill transport of oligopeptides and peptide-like drugs such as beta-lactam antibiotics in the intestinal and renal brush-border membranes. Two H+/peptide cotransporters, PEPT1 and PEPT2, have been cloned and functionally characterized. In this study, we examined the interaction of the dipeptides and beta-lactam antibiotics with the histidine residue of rat PEPT1 and PEPT2 transfected into the renal epithelial cell line LLC-PK1. Diethylpyrocarbonate (DEPC), which is a histidine residue modifier, abolished the glycylsarcosine uptake by both transfectants. The DEPC-induced inhibition of glycylsarcosine uptake via PEPT1 or PEPT2 was attenuated by an excess of dipeptide or aminocephalosporin. In contrast, anionic cephalosporins without an alpha-amino group and bestatin, which is an antineoplastic drug with a beta-amino group, did not attenuate the DEPC-induced inactivation of PEPT1 and PEPT2. The DEPC inactivation of PEPT1 was almost prevented by various charged dipeptides, which suggests that the inability of the drugs without an alpha-amino group to prevent the DEPC inactivation was not due to their ionic charge. These findings suggest that the alpha-amino group of beta-lactam antibiotics interacts with the histidine residue of PEPT1 and PEPT2 and may be involved in the mechanism of substrate recognition by the peptide transporters.
authors.affiliation: Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto 606-01, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Terada
authors.forename: H
authors.initials: H
authors.lastname: Saito
authors.forename: K
authors.initials: K
authors.lastname: Inui
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism; D001665:Binding Sites; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D002511:Cephalosporins / Q000494:pharmacology; D004047:Diethyl Pyrocarbonate / Q000494:pharmacology; D004151:Dipeptides / Q000493:pharmacokinetics / Q000494:pharmacology; D006639:Histidine / Q000378:metabolism; D007668:Kidney / Q000502:physiology; D000074011:Peptide Transporter 1; D051381:Rats; D027981:Symporters; D014162:Transfection / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D002352:Carrier Proteins; D002511:Cephalosporins; D004151:Dipeptides; D000074011:Peptide Transporter 1; C489940:Slc15a1 protein, rat; D027981:Symporters; C093694:hydrogen-coupled oligopeptide transporter PepT2; C004194:glycylsarcosine; D006639:Histidine; D004047:Diethyl Pyrocarbonate