Comparative studies on the nephrotoxicity of 2-bromoethanamine hydrobromide in the Fischer 344 rat and the multimammate desert mouse (Mastomys natalensis)

Abstract

Renal papillary necrosis (RPN) was induced in Fischer 344 (F344) rats (n=4) using 2-bromoethanamine hydrobromide (BEA) dosed at 150 mg/kg, and in multimammate desert mice (Mastomys natalensis) at 150 and 250 mg/kg (n=4) per group). Control rats andMastomys were dosed with 0.9% saline (n=4 per group). Urine was collected at regular intervals for up to 4 days post-dosing and analysed for low MW metabolites using high resolution¹H NMR spectroscopy. The urinary activity of lactate dehydrogenase, γ-glutamyl transpeptidase and alkaline phosphatase was determined using conventional biochemical assays. On termination, histopathological examination of papillae was performed showing the development of extensive lesions in F344 rats at 150 mg/kg BEA.Mastomys appeared much more resistant to BEA and showed normal renal histology at 150 mg/kg and patchy lesions at 250 mg/kg BEA. Enzyme analysis of control urine showed F344 rats to have > 1000% higher γ-glutamyl transpeptidase activity thanMastomys.¹H NMR spectroscopic analysis showed that BEA caused a substantial decrease in urinary concentrations of succinate and citrate (0–24 h p.d.) and an increase in creatine (0–96 h p.d.) in both animal models. A decrease in the urinary concentration of 2-oxoglutarate with a subsequent increase by 72–96 h p.d. was also noted in both animal models. Glutaric and adipic aciduria were also induced in both F344 rats andMastomys 0–24 h post-BEA treatment, indicative of an enzyme deficiency in the acyl CoA dehydrogenases. Urinary taurine levels were elevated inMastomys following the administration of BEA, indicating some degree of liver toxicity. Urinary taurine was not elevated in F344 rats following BEA administration, demonstrating further species difference in BEA toxicity.