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Petiz 2018 Chem Biol Interact

From Bioblast
Publications in the MiPMap
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.

ยป PMID: 29128607

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 ฮผM) 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 โˆผ15%. 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 โˆผ32% and โˆผ43% 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 โˆผ69% (65 nmol mg-1 of protein) and an increase in ATPase activity in intact mitochondria by โˆผ27% and โˆผ83% 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 โˆผ16% 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 โˆผ20% 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. โ€ข Keywords: ATPase activity, Amidine derivatives, Liver mitochondria, Methoxyamidine, Mitochondrial swelling, Respiratory chain enzymes โ€ข 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