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Gentamicin inhibits carrier-mediated dipeptide transport in kidney
H A Skopicki1, D Zikos, E J Sukowski
1Department of Physiology and Biophysics, Finch University of Health Sciences, Chicago Medical School 60064, USA.
Abstract:
The effect of gentamicin on transport of pyroglutamylhistidine (pGlu-His) was examined in rabbit renal brush-border membrane vesicles (BBMV). Gentamicin, an aminoglycoside antibiotic, is limited in its usage because of nephrotoxicity characterized in part by transport defects in the proximal tubule. Since there is no information regarding the effects of gentamicin on renal peptide carriers, uptake of [3H]pGlu-His was measured in BBMV following either in vivo or in vitro exposure to the antibiotic. One hour after in vivo administration, the maximal rate (Vmax) for pGlu-His transport was significantly reduced in isolated membrane vesicles washed free of the drug, but the apparent Michaelis constant (Km) was unaltered. Coincubation of membranes with gentamicin during measurements of pGlu-His uptake had a similar effect, causing a significant decrease in the Vmax but not the Km of transport. The addition of 5 mM magnesium to the uptake medium prevented the in vitro but not the in vivo effect. The data indicate that high doses of gentamicin inhibit the capacity but not the affinity of dipeptide transport in the kidney, prior to morphological changes which typify acute tubular necrosis. The in vitro effect is rapid and involves a direct action of gentamicin on the brush-border membrane. The in vivo experiments show that toxicity may be prolonged and remains following removal of the drug from the renal brush border.
Insights
Gentamicin, an antibiotic, impairs kidney peptide transport by reducing its capacity, not affinity. This occurs rapidly and can persist even after the drug is removed, contributing to nephrotoxicity.
Area of Science:
- Nephrology
- Pharmacology
- Molecular Biology
Background:
- Gentamicin, an aminoglycoside antibiotic, can cause nephrotoxicity.
- Nephrotoxicity is partly due to impaired transport in the kidney's proximal tubule.
- The effects of gentamicin on renal peptide carriers are not well understood.
Purpose of the Study:
- To investigate the impact of gentamicin on pyroglutamylhistidine (pGlu-His) transport.
- To determine if gentamicin affects the affinity or capacity of renal peptide transport.
- To differentiate between in vivo and in vitro effects of gentamicin on kidney brush-border membranes.
Main Methods:
- Utilized rabbit renal brush-border membrane vesicles (BBMV).
- Measured uptake of radiolabeled [3H]pGlu-His after in vivo or in vitro gentamicin exposure.
- Assessed changes in transport kinetics (Vmax and Km) with and without magnesium.
Main Results:
- In vivo gentamicin administration significantly reduced the maximal transport rate (Vmax) of pGlu-His.
- In vitro gentamicin exposure also decreased Vmax without altering the Michaelis constant (Km).
- Magnesium ions prevented the in vitro effect but not the in vivo effect.
Conclusions:
- Gentamicin inhibits the capacity, not the affinity, of dipeptide transport in the kidney.
- The in vitro effect is rapid and directly impacts the brush-border membrane.
- In vivo toxicity is prolonged and persists after gentamicin removal, preceding morphological damage.