Trypanocidal napthoimidazoles: studies on mitochondrial rat liver toxicity and mutagenicity

CASANOVA MB,ELINGOLD I, CELENTANO AM, DE CASTRO SL, DUBIN M

Buenos Aires, Facultad de Medicina ,UBA

Congreso; Sociedad Argentina de Farmacología Experimental; 2007

Sociedad Argentina de Farmacología Experimental

Trypanocidal naphthoimidazoles: Studies on mitochondrial rat liver toxicity and mutagenicity Casanova MB, Elingold I, Celentano AM1, Menna-Barreto R2, Ventura-Pinto A3, Chan A4, Nagel R4, de Castro SL2, Dubin M. CEFYBO UBA-CONICET, Dptos. 1Microbiología, Fac. Medicina,2Instituto Oswaldo Cruz, 3Universidade Federal do Rio de Janeiro, Río de Janeiro, Brasil, 4 INAME-Ministerio de Salud. dubin @mail.retina.ar Naphthoimidazole (NPH)  derivatives from β-lapachone: N1, N2 and N3, were shown to have important trypanocidal activity. The aim of this study was the evaluation of the mitochondrial rat liver toxicity and the potential mutagenicity of these compounds. It was found that N1 and N3 (25 and 50μM) produced a significant increase in oxygen uptake with succinate (site II substrate) and mitochondria in metabolic state 4 (resting respiration). On the other hand, state 3 (active respiration) was not modified. Also the respiratory control index (RCI) decreased significantly in the presence of either N1 (25 and 50μM) or N3 (10, 25 and 50μM). Mitochondrial membrane potential (MMP) was measured by rhodamine 123 fluorescence with malate-glutamate as substrate.  Both, N1 (50μM) and N3 (50 μM) decreased significantly this parameter after 25 min. incubation 69,9 and 72,8 %, respectively. N2 addition did not significantly modify the respiratory states, RCI or MMP. None of the three NPH was found to be mutagenic when assayed with the Salmonella/microsome test.  From these results it can be concluded that of the three NPH studied, N2, because its lack of toxicity, can be considered as the most potentially effective agent for Chagas chemoterapy.