COMPARATIVE-STUDIES ON THE NEPHROTOXICITY OF 2-BROMOETHANAMINE HYDROBROMIDE IN THE FISCHER-344 RAT AND THE MULTIMAMMATE DESERT MOUSE (MASTOMYS-NATALENSIS)

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 and Mastomys were dosed with 0.9 % saline (n = 4 per group). Urine was collected at regular intervals f or up to 4 days post-dosing and analysed for low MW metabolites using high resolution H-1 NMR spectroscopy. The urinary activity of lactate dehydrogenase, gamma-glutamyl transpeptidase and alkaline phosphatase was determined using conventional biochemical assays. On termination, histopathological examination of papillae was performed showing the de velopment 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 gamma-glutamyl t ranspeptidase activity than Mastomys. H-1 NMR spectroscopic analysis s howed 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 concentra tion 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 al so induced in both F344 rats and Mastomys 0-24 h post-BEA treatment, i ndicative of an enzyme deficiency in the acyl CoA dehydrogenases. Urin ary taurine levels were elevated in Mastomys following the administrat ion of BEA, indicating some degree of liver toxicity. Urinary taurine was not elevated in F344 rats following BEA administration, demonstrat ing further species difference in BEA toxicity.