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Nephrotoxicity and uptake of 1-benzyl quinolinium in precision-cut rabbit renal cortical slices
H V Sheevers1, K Brendel, S H Wright
1Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85724, USA.
Abstract:
Nephrotoxicity studies have not always meshed toxicity with transport and uptake, although the two are interdependent. To begin to address this issue, a series of model organic cations (quaternary amines) was examined which revealed differences in toxicity that were not explained by slight structural variations. Thus, a single model organic cation, 1-benzyl quinolinium (BQ), was used to assess organic cations in rabbit renal cortical slices. Histopathological evaluation revealed that BQ produced site-specific injury in the S(3) region of the proximal tubule. Biochemical assays (K(+), qO(2) and ATP) revealed dose- and time-dependent decreases of BQ-exposed slices over 2-12 hr. Cation transport (uptake of tetraethylammonium) was decreased by BQ at sub-toxic doses within 2 hr, although anion transport (uptake of p-aminohippurate) was not affected. Understanding the toxicity and transport of model cations such as BQ will help to identify the mechanisms associated with organic cation nephrotoxicity as well as to facilitate the use of transport parameters to prevent toxicity or prolong drug action of cations.
Insights
1-benzyl quinolinium (BQ) causes site-specific kidney injury and impairs organic cation transport at sub-toxic doses. This research links nephrotoxicity mechanisms to transport processes for organic cations.
Area of Science:
- Renal toxicology
- Pharmacokinetics
- Cellular transport mechanisms
Background:
- Nephrotoxicity research often overlooks the interplay between toxicity and cellular transport.
- Understanding organic cation handling by the kidney is crucial for predicting drug-induced kidney damage.
Purpose of the Study:
- To investigate the nephrotoxic effects of organic cations, specifically 1-benzyl quinolinium (BQ).
- To determine the relationship between BQ's toxicity and its impact on renal cation and anion transport.
Main Methods:
- Rabbit renal cortical slices were exposed to varying doses and durations of BQ.
- Histopathological analysis assessed tissue damage.
- Biochemical assays measured potassium levels, oxygen consumption, and ATP content.
- Cation (tetraethylammonium) and anion (p-aminohippurate) uptake were quantified.
Main Results:
- BQ induced site-specific injury in the S(3) segment of the proximal tubule.
- Biochemical markers (K+, qO(2), ATP) decreased in a dose- and time-dependent manner following BQ exposure.
- BQ significantly reduced cation transport at sub-toxic concentrations within 2 hours.
- Anion transport remained unaffected by BQ treatment.
Conclusions:
- 1-benzyl quinolinium (BQ) is nephrotoxic, targeting the S(3) proximal tubule region.
- BQ impairs organic cation transport at doses below those causing overt toxicity.
- These findings highlight the importance of considering transport dynamics in organic cation nephrotoxicity and offer potential strategies for toxicity mitigation.
