| Autor: |
Andrianov VV; Zavoisky Physical-Technical Institute of the Russian Academy of Sciences, Kazan 420029, Russia.; Department of Human and Animal Physiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia., Schepetkin IA; Kizhner Research Center, Tomsk Polytechnic University, Tomsk 634050, Russia.; Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT 59717, USA., Bazan LV; Zavoisky Physical-Technical Institute of the Russian Academy of Sciences, Kazan 420029, Russia., Gainutdinov KL; Zavoisky Physical-Technical Institute of the Russian Academy of Sciences, Kazan 420029, Russia.; Department of Human and Animal Physiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia., Kovrizhina AR; Kizhner Research Center, Tomsk Polytechnic University, Tomsk 634050, Russia., Atochin DN; Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02115, USA., Khlebnikov AI; Kizhner Research Center, Tomsk Polytechnic University, Tomsk 634050, Russia. |
| Abstrakt: |
IQ-1 (11 H -indeno[1,2- b ]quinoxalin-11-one oxime) is a specific c-Jun N-terminal kinase (JNK) inhibitor with anticancer and neuro- and cardioprotective properties. Because aryloxime derivatives undergo cytochrome P450-catalyzed oxidation to nitric oxide (NO) and ketones in liver microsomes, NO formation may be an additional mechanism of IQ-1 pharmacological action. In the present study, electron paramagnetic resonance (EPR) of the Fe 2+ complex with diethyldithiocarbamate (DETC) as a spin trap and hemoglobin (Hb) was used to detect NO formation from IQ-1 in the liver and blood of rats, respectively, after IQ-1 intraperitoneal administration (50 mg/kg). Introducing the spin trap and IQ-1 led to signal characteristics of the complex (DETC) 2 -Fe 2+ -NO in rat liver. Similarly, the introduction of the spin trap components and IQ-1 resulted in an increase in the Hb-NO signal for both the R- and the T-conformers in blood samples. The density functional theory (DFT) calculations were in accordance with the experimental data and indicated that the NO formation of IQ-1 through the action of superoxide anion radical is thermodynamically favorable. We conclude that the administration of IQ-1 releases NO during its oxidoreductive bioconversion in vivo . |
