Petiz 2018 Chem Biol Interact
Petiz LL, Pires ADRA, Echevarria A, Rodrigues-Santos CE, Eliane Merlin Rocha M, Acco A, Cadena SMSC (2018) Effects of a new antiprotozoal drug, N,N'-diphenyl-4-methoxy-benzamidine, on energy-linked functions of rat liver mitochondria. Chem Biol Interact 279:34-42. |
Petiz LL, Pires ADRA, Echevarria A, Rodrigues-Santos CE, Eliane Merlin Rocha M, Acco A, Cadena SMSC (2018) Chem Biol Interact
Abstract: Amidines are chemically characterized by the presence of two nitrogen atoms that bind to the same carbon atom in its structure. Several biological activities have been ascribed to these compounds. Pentamidine, an aromatic diamidine, is effective in the treatment against Pneumocystis carinii and leishmaniasis, but it can also have severe side effects. New amidine derivatives have been synthesized, among them N,N'-diphenyl-4-methoxy-benzamidine (methoxyamidine), which is effective against Leishmania amazonensis (LD50 = 20 ΞΌM) and Trypanosoma cruzi (LD50 = 59 nM). In the present study, methoxyamidine toxicity was evaluated in isolated rat liver mitochondria at the same range of concentrations that exert antiprotozoal activity. In these organelles, actively oxidizing glutamate + malate inhibited state 3 respiration (25 nmol mg-1 of protein) by βΌ15%. The sites of inhibition in the respiratory chain were complex I and the segment between ubiquinone and complex III. Methoxyamidine also stimulated state 4 respiration by βΌ32% and βΌ43% at 50 and 65 nmol mg-1 of protein, respectively. Its uncoupling effect was confirmed by a dose-dependent increase in oxygen consumption in state 4 respiration that was induced by oligomycin, reaching up to βΌ69% (65 nmol mg-1 of protein) and an increase in ATPase activity in intact mitochondria by βΌ27% and βΌ83% at 50 and 65 nmol mg-1 protein, respectively. Swelling that was supported by the oxidation of glutamate + malate in the presence of sodium acetate was reduced by methoxyamidine by βΌ16% and 32% at 50 and 65 nmol mg-1 protein, respectively. Mitochondrial swelling in the absence of substrate and in the presence of K+ and valinomycin was inhibited by βΌ20% at the same concentrations, suggesting that methoxyamidine affects mitochondrial membrane permeability and fluidity. Our data show that methoxyamidine has slight effects on the energy-linked functions of isolated mitochondria at concentrations that correspond to the LD50 against Leishmania amazonensis and Trypanosoma cruzi. These findings may prompt further studies that evaluate methoxyamidine toxicity in vivo. β’ Keywords: ATPase activity, Amidine derivatives, Liver mitochondria, Methoxyamidine, Mitochondrial swelling, Respiratory chain enzymes β’ Bioblast editor: Kandolf G
Labels: MiParea: Respiration, mt-Medicine, Pharmacology;toxicology
Organism: Rat
Tissue;cell: Liver
Preparation: Isolated mitochondria
Coupling state: LEAK, OXPHOS, ET
Pathway: N, S, NS, ROX
HRR: Oxygraph-2k
Labels, 2018-01