Several halogenated alkanes used as industrial solvents, soil fumigants, flame retardants, and lead scavengers are highly nephrotoxic chemicals in humans. In experimental animals, the halogenated compound 2-bromoethylamine (BEA), that induces acute renal failure associated with renal papillary necrosis and cortex damage, has been used as a model agent to study the molecular mechanism underlying kidney injury.

BEA exhibits high chemical reactivity and in an aqueous solution, the bromide ion rapidly dissociates, because the alkyl moiety is able to form the stressed, three-membered aziridine ring of ethyleneimine, a potent alkylating agent with papillotoxic properties. It was suggested that papillotoxic doses of BEA could produce sufficient amounts of ethyleneimine in vivo to induce papillary necrosis, thereby ascribing the renal toxicity of BEA to its alkylating potential. Alternatively, the oxidative stress mechanism of cell injury also seems to be involved in the toxic actions of BEA on the kidney. The morphological changes induced by BEA occurred concomitantly with GSH depletion and an increase in the proliferative activity of the kidney Both these effects are abolished by N-acetyl-L-cysteine pretreatment. Reactive oxygen species (ROS) have been proposed to cause oxidative damage to biomolecules and to be involved in the development of several human and experimental renal disorders, whereas both resident renal cells and circulating cells could represent potential sources of ROS. Damage by ROS is determined not only by the rate of oxyradical generation, but also by the antioxidant status of the cells, which might explain the differential susceptibility of different organs, or that of various cell types within a given organ, to oxidative injury.

In view of these considerations, the present work was undertaken to assess the role of oxidative stress in the renal toxicity induced by BEA. For this purpose, the activity of antioxidant enzyme superoxide dismutase (SOD), catalase, and glutathione peroxidase (GSH-Px), as well as the cellular content of non-protein sulfhydryls (NPSH) were measured following BEA administration to rats in relation to the lipid peroxidative potential of renal tissue. Measurements were done, and these indicators were assessed, both in renal cortex and papilla segments which exhibit differential distribution of NPSH levels and in the activity of the enzymes related to glutathione metabolism.

Results

BEA administration on renal SOD activity. As can be observed, no significant differences in SOD activity were found between renal cortex and papilla from control rats. BEA induced a marked decrease in papillary SOD activity at 15 h and at 24 h after treatment (p <0.001), whereas that of the renal cortex SOD activity was significantly increased at 15 h (p <0.001) and comparable to control values at 24 h. Renal catalase activity in control animals was significantly higher in cortex than papilla. The activity of cortical catalase was not modified 1.5 h after BEA treatment, being significantly lower than basal values at 15 and 24 h. In papillary tissue, an early decrease in catalase activity was observed 1.5 h after BEA administration, with a higher diminution being elicited at 24 h. Maximal decreasing effects in catalase activity in cortex and papilla at 24 h after BEA treatment were 30% and 70%, respectively. Basal activity of GSH-Px was significantly higher (p <0.001) in cortex than in papilla. GSH-Px was diminished by 44% and 77% in cortex and papilla, respectively (p <0.001), 15 h after BEA administration, an effect that persisted in the renal papilla at 24 h, whereas that in the cortex was recovered to control values.

The basal content of NPSH in renal papilla was about 50% of that found in the cortex. BEA significantly decreased cortical NPSH levels by 20% at 1.5–6 h after treatment, which was comparable to control values at 15 and 24 h. In the papilla, NPSH depletion (27%) was observed only at 6 and 15 h after BEA intoxication. Basal values of MDA production in renal papilla were 22% (p <0.01) of those in the cortex. Following BEA administration, papillary MDA formation increased by 2.9-fold at 1.5 h, dropped to control values at 6 h, and was diminished below basal levels at 24 h. In renal cortex, a significant increase in MDA formation was observed only at 24 h after BEA treatment.