Abstract
Catecholamine neurotransmitters such as norepinephrine, dopamine, and related catecholamine derivatives reduce nitroheterocyclic drugs such as nitrofurantoin, nifurtimox, nifuroxime, nitrofurazone, misonidazole, and metronidazole in slightly alkaline solutions. Drugs which contain 5-nitrofurans are reduced at lower pH than drugs which contain 2- and 5-nitroimidazoles. 5-Nitroimidazole derivatives such as metronidazole and ronidazole are known to be more difficult to reduce than 2-nitroimidazole derivatives, due to their lower redox potential. Catecholamines, when reducing nitro drugs, undergo concomitant oxidation to form semiquinone radicals. Both semiquinone radicals and nitro anion radicals formed in a reaction of nitro drug and catecholamine derivative were detected by electron spin resonance spectroscopy. Oxygen consumption studies in solutions containing nitro drug and catecholamine derivative showed that nitro anion radicals formed under aerobic conditions reduce oxygen to form the superoxide radical and hydrogen peroxide. Quinones formed in the reaction of catecholamine and nitro drug were detected by optical spectroscopy. Biosynthetic precursors and some metabolic products of catecholamines were also used in these studies, and they all exhibited reactions similar to catecholamines. Bovine chromaffin granules which synthesize and store catecholamines produced the nitrofurantoin anion radical when intact granules were treated with nitrofurantoin. These radicals formed inside the granules were observed by ESR spectroscopy. The formation of nitrofurantoin radical, semiquinone radicals of catecholamines, and oxygen-derived radicals by chromaffin granules is proposed to cause damage to adrenal medulla, and this process may lead to neurotoxicity.
Highlights
Catecholamine neurotransmitters such as norepi- [10, 11].At lower doses nitrofurantoin is used as a urinary nephrine, dopamine, and relatedcatecholamine deriv- antiseptic [12], while metronidazole is used for amebic dysatives reduce nitroheterocyclic drugsusch as nitrofur- entery andfor protozoal and bacterial infections of the vagina antoin, nifurtimox, nifuroxime, nitrofurazone, mison- [13,14,15]
Nitrofurans such as nitrofurantoin, nifurtimox, nifuroxime, The hyperfinecoupling constants reported in this papewrere and nitrofurazone to their corresponding nitro anraidoincals. obtained by the correlation technique [29], and gave much
The nitro anion radical of nitrofurantoin was observed at a formation of nitro anion and semiquinone radicalsby the concentration of 2.5 mM of norepinephrine when the solution catecholamine reductionof nitroheterocyclic drugs. was slightly alkaline, i.e. at p H 9.2
Summary
From the Laboratory of Molecular Biophysics, National Instituteof Environmental HealthSciences, Research Triangle Park, North Carolina27709 Catecholamine neurotransmitters such as norepi- [10, 11].At lower doses nitrofurantoin is used as a urinary nephrine, dopamine, and relatedcatecholamine deriv- antiseptic [12], while metronidazole is used for amebic dysatives reduce nitroheterocyclic drugsusch as nitrofur- entery andfor protozoal and bacterial infections of the vagina antoin, nifurtimox, nifuroxime, nitrofurazone, mison- [13,14,15]. Nitro anion radicals produced can be further reduced under hypoxic conditions to form their corresponding nitroso, hydronitroxide, and aminecompounds [4,15]. Store catecholamines produced the nitrofurantoin anion radical when intact granules were treated with nitrofurantoin
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