RGD Reference Report - beta-lactam antibiotics as substrates for OCTN2, an organic cation/carnitine transporter. - Rat Genome Database

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beta-lactam antibiotics as substrates for OCTN2, an organic cation/carnitine transporter.

Authors: Ganapathy, ME  Huang, W  Rajan, DP  Carter, AL  Sugawara, M  Iseki, K  Leibach, FH  Ganapathy, V 
Citation: Ganapathy ME, etal., J Biol Chem. 2000 Jan 21;275(3):1699-707.
RGD ID: 1643135
Pubmed: PMID:10636865   (View Abstract at PubMed)

Therapeutic use of cephaloridine, a beta-lactam antibiotic, in humans is associated with carnitine deficiency. A potential mechanism for the development of carnitine deficiency is competition between cephaloridine and carnitine for the renal reabsorptive process. OCTN2 is an organic cation/carnitine transporter that is responsible for Na(+)-coupled transport of carnitine in the kidney and other tissues. We investigated the interaction of several beta-lactam antibiotics with OCTN2 using human cell lines that express the transporter constitutively as well as using cloned human and rat OCTN2s expressed heterologously in human cell lines. The beta-lactam antibiotics cephaloridine, cefoselis, cefepime, and cefluprenam were found to inhibit OCTN2-mediated carnitine transport. These antibiotics possess a quaternary nitrogen as does carnitine. Several other beta-lactam antibiotics that do not possess this structural feature did not interact with OCTN2. The interaction of cephaloridine with OCTN2 is competitive with respect to carnitine. Interestingly, many of the beta-lactam antibiotics that were not recognized by OCTN2 were good substrates for the H(+)-coupled peptide transporters PEPT1 and PEPT2. In contrast, cephaloridine, cefoselis, cefepime, and cefluprenam, which were recognized by OCTN2, did not interact with PEPT1 and PEPT2. The interaction of cephaloridine with OCTN2 was Na(+)-dependent, whereas the interaction of cefoselis and cefepime with OCTN2 was largely Na(+)-independent. Furthermore, the Na(+)-dependent, OCTN2-mediated cellular uptake of cephaloridine could be demonstrated by direct uptake measurements. These studies show that OCTN2 plays a crucial role in the pharmacokinetics and therapeutic efficacy of certain beta-lactam antibiotics such as cephaloridine and that cephaloridine-induced carnitine deficiency is likely to be due to inhibition of carnitine reabsorption in the kidney.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Slc22a5Ratcarnitine transport  IDA sodium-dependentRGD 
Slc15a2Ratdipeptide transport  IDA glycylsarcosine and proton-dependentRGD 
Slc22a5Ratquaternary ammonium group transport  IDA  RGD 

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Slc22a5Ratcarnitine transmembrane transporter activity  IDA sodium-dependentRGD 
Slc15a2Ratdipeptide transmembrane transporter activity  IDA glycylsarcosine and proton-dependentRGD 
Slc22a5Ratquaternary ammonium group transmembrane transporter activity  IDA  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Slc15a2  (solute carrier family 15 member 2)
Slc22a5  (solute carrier family 22 member 5)


Additional Information