Redox-cycling Drugs Research Articles

Exogenous quinones directly inhibit the respiratory NADH dehydrogenase in Escherichia coli

The ability of naphthoquinones to generate reactive oxygen species has been widely exploited in studies of oxidative stress. However, excess superoxide dismutase and catalase failed to protect Escherichia coli in rich medium against growth inhibition by plumbagin, indicating that its toxic effect was not due to the production of partially reduced oxygen species. Respiration failed immediately upon the addition of growth-inhibitory levels of plumbagin. Studies in vitro showed that plumbagin and other redox-active quinones intercept electrons from NADH dehydrogenase, the primary respiratory dehydrogenase in glucose-containing media. An excess of oxidative substrate, such as plumbagin, inactivates this enzyme, which appears to be redox-regulated. The resultant respiratory arrest is a cautionary example of metabolic dysfunction from redox-cycling drugs that cannot be attributed to superoxide or hydrogen peroxide.

Null mutants of Saccharomyces cerevisiae Cu,Zn superoxide dismutase: characterization and spontaneous mutation rates

Deletion-replacement mutations of the Saccharomyces cerevisiae Cu,Zn superoxide dismutase gene were constructed. They were exquisitely sensitive to redox cycling drugs and showed slight sensitivity to other agents. The aerobic spontaneous mutation rate was three- to fourfold higher in sod1 delta 1 mutants, while the anaerobic rate was similar to that of the wild type.

Comparative studies of nifurtimox uptake and metabolism by drug-resistant and susceptible strains of Trypanosoma cruzi

1. Nifurtimox uptake and metabolism by epimastigote forms of three strains of Trypanosoma cruzi (Basileu, Y, YuYu) with different drug responsiveness in mice experimental infections were compared. 2. Statistical analysis of the results demonstrated no correlation between the ability of the strains to catalyze nifurtimox redox-cycling (Basileu = Y = YuYu) nor nifurtimox multiple electron reduction (Basileu = Y > Y) and drug susceptibility (Basileu > Y > YuYu). 3. A partial correlation however, was observed between drug responsiveness and nifurtimox uptake (Basileu > Y = YuYu). 4. The results suggest that drug uptake may be more important than drug metabolism in modulating resistance to nifurtimox in T. Cruzi strains.

Renal toxicity of antineoplastic agents

Most of the drugs currently used in the treatment of cancer are highly cytotoxic and possess relatively low therapeutic selectivity. Given the major role of the kidney in the excretion of these drugs or their metabolites, it is perhaps surprising that clinically significant nephrotoxicity occurs with a limited number of drugs. Adriamycin induces a nephrotic syndrome in rats characterized by severe acute glomerular injury and sustained proteinuria. Tubular lesions subsequently develop, and the formation of tubular casts with resulting interstitial changes is accompanied by the appearance of glomerulosclerosis. Although the mechanism of adriamycin-induced nephrotoxicity is not known, it has been suggested that redox cycling may contribute to this toxicity by enhancing membrane lipid peroxidation, resulting in damage to kidney endoplasmic reticulum and mitochondrial membranes [l]. Mitocycin C is another redox-cycling drug with a cytotoxic mechanism of action that is very different from adriamycin. A hemolytic uremic syndrome of unknown pathogenesis has been reported in some patients treated with mitomycin C; this syndrome has been reproduced in’a unilateral perfusion study in the rat [2]. Nephrotoxicity has been reported for the nitrosoureas in both clinical and laboratory studies. Methyl-CCNU administered as a single, high dose produces acute proximal tubular necrosis in the rat; impaired tubular transport was evident 1 h after drug treatment. Proteinuria and decreased urine-concentrating ability accompanied necrosis of the papillary collecting ducts l-6 days later. Low-dose treatment resulted in a delayed-onset chronic progressive nephropathy involving polyuria, enzymuria, and decreased urine-concentrating ability [3,4]. Several lines of evidence point to the

AD 5, a dehydroalanine derivative, decreases the amount of reactive oxygen species formed during nitrofurantion microsomal metabolism

N-acyl dehydroalanines have been shown to react with and scavenge oxygen derived free radicals. One of those compounds, the AD-5 (N-(paramethoxyphenylacetyl) dehydroalanine) has been examined for its ability to decrease the amount of reactive oxygen species which appeared when liver microsomes (isolated from rats pretreated with phenobarbital) are incubated in the presence of Nitrofurantoin (NF). This molecule was used as a model compound in order to stimulate the production of superoxide anion and hydrogen peroxide, as well as to enhance the oxidation of NADPH and the oxygen uptake. These two later parameters were not modified when adding AD-5 to microsomes incubated in the presence of NF. However, in such conditions the amount of both and hydrogen peroxide was decreased. These effects were dose-dependent. These data suggest that AD 5 inhibits the building up of superoxide and consequently the production of hydrogen peroxide. We postulate that AD-5 acting as an oxygen derived free radical scavenger, can be used to inhibit the oxidative injury induced by nitrofurantoin and other redox cycling drugs.

A survey of chemicals inducing lipid peroxidation in biological systems

A great number of drugs and chemicals are reviewed which have been shown to stimulate lipid peroxidation in any biological system. The underlying mechanisms, as far as known, are also dealt with. Lipid peroxidation induced by iron ions, organic hydroperoxides, halogenated hydrocarbons, redox cycling drugs, glutathione depleting chemicals, ethanol, heavy metals, ozone, nitrogen dioxide and a number of miscellaneous compounds, e.g. hydrazines, pesticides, antibiotics, are mentioned. It is shown that lipid peroxidation is stimulated by many of these compounds. However, quantitative estimates cannot be given yet and it is still impossible to judge the biological relevance of chemical-induced lipid peroxidation.

Biochemical mechanism of oxidative damage by redox-cycling drugs.

Biochemical mechanisms of production of redox intermediates of redox-cycling drugs include: photochemical events, either photoionization process or electron transfer from photoexcited states; electron exchange of reduced form of a drug with the oxy state of oxygen-binding hemoproteins; oxidation by catalytic metal centers (oxidases, peroxidases, oxygenases) of the reduced forms of drugs; or electron transfer to the oxidized form of a drug from activated intracellular electron transfer chain (mitochondria, microsomes, etc.). Further reaction of these drug free radicals can lead to oxidative damage by either direct attack of biological macromolecules or via oxygen reduction, giving O2-, H2O2, and OH. The reaction pathway depends on the presence of metal ions, natural scavengers, enzymes that control relative concentrations of reactive species, and availability of oxygen in the environment.

Biochemical Mechanism of Oxidative Damage by Redox-Cycling Drugs

Biochemical mechanisms of production of redox intermediates of redox-cycling drugs include: photochemical events, either photoionization process or electron transfer from photoexcited states; electron exchange of reduced form of a drug with the oxy state of oxygen-binding hemoproteins; oxidation by catalytic metal centers (oxidases, peroxidases, oxygenases) of the reduced forms of drugs; or electron transfer to the oxidized form of a drug from activated intracellular electron transfer chain (mitochondria, microsomes, etc.). Further reaction of these drug free radicals can lead to oxidative damage by either direct attack of biological macromolecules or via oxygen reduction, giving O2-, H2O2, and OH. The reaction pathway depends on the presence of metal ions, natural scavengers, enzymes that control relative concentrations of reactive species, and availability of oxygen in the environment.