Toxicity and transport of organic cations in the rabbit kidney

Abstract

The kidney is often the target of toxicants, although the precise mechanisms of nephrotoxicity are often not clear. Renal transport is an important part of toxic mechanisms, and transport, especially of organic cations, has not been well incorporated into nephrotoxicity studies. The transport of anionic toxins into target cells has been shown to be crucial in producing toxicity in renal cortical slices. However, organic cations and their transport in renal toxicity have not been fully examined. Only a small amount of information exists on organic cation nephrotoxicity and transport. This investigation represents a step in developing a greater understanding of nephrotoxic mechanisms associated with organic cations and their transport in the rabbit renal cortex. Model organic cations were first evaluated, and the investigation then focused on one, 1-benzyl quinolinium (BQ). BQ, chosen as the model compound due to its nephrotoxic potential and its interactions at the organic cation transporter, was studied in renal cortical slices, proximal tubules in suspension, and in cortical mitochondria. Toxicity studies demonstrated that BQ was nephrotoxic, and site specific toxicity was noted at the proximal tubule using light microscopy. The effects of BQ on mitochondrial preparations and tubules in suspension suggested that BQ uncoupled mitochondrial oxidative phosphorylation. Studies in slices indicated BQ had great affinity for the organic cation transporter site. Follow-up evaluations using fluorometric quantification suggested that BQ accumulation involves the organic cation transporter; and that BQ may be taken up by both active and passive transport mechanisms. Understanding the toxicity and transport of cations like BQ will help determine the mechanisms associated with organic cation nephrotoxicity and may be used to facilitate the application of transport parameters to prevent toxicity of nephrotoxic cations.