Indian propolis ameliorates the mitomycin C-induced testicular toxicity by reducing DNA damage and elevating the antioxidant activity

Bacterial chromosomes harbor toxin-antitoxin (TA) systems, some of which are implicated in the formation of multidrug-tolerant persister cells. In Escherichia coli, toxin TisB from the tisB/istR-1 TA system depolarizes the inner membrane and causes ATP depletion, which presumably favors persister formation. Transcription of tisB is induced upon DNA damage due to activation of the SOS response by LexA degradation. Transcriptional activation of tisB is counteracted on the post-transcriptional level by structural features of tisB mRNA and RNA antitoxin IstR-1. Deletion of the regulatory RNA elements (mutant Δ1-41 ΔistR) uncouples TisB expression from LexA-dependent SOS induction and causes a ‘high persistence’ (hip) phenotype upon treatment with different antibiotics. Here, we demonstrate by the use of fluorescent reporters that TisB overexpression in mutant Δ1-41 ΔistR inhibits cellular processes, including the expression of SOS genes. The failure in SOS gene expression does not affect the hip phenotype upon treatment with the fluoroquinolone ciprofloxacin, likely because ATP depletion avoids strong DNA damage. By contrast, Δ1-41 ΔistR cells are highly susceptible to the DNA cross-linker mitomycin C, likely because the expression of SOS-dependent repair systems is impeded. Hence, the hip phenotype of the mutant is conditional and strongly depends on the DNA-damaging agent.

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The sir locus of Escherichia coli: a gene involved in SOS-independent repair of mitomycin C-induced DNA damage

Mutation Research/DNA Repair ◽

10.1016/0921-8777(90)90061-9 ◽

1990 ◽

Vol 235 (2) ◽

pp. 85-92 ◽

Cited By ~ 4

Author(s):

K.R. Kumaresan ◽

R. Jayaraman

Keyword(s):

Escherichia Coli ◽

Dna Damage ◽

Mitomycin C

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Evaluation of the Protective Effects of Quercetin, Rutin, Naringenin, Resveratrol and Trolox Against Idarubicin-Induced DNA Damage

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/j3s01g ◽

2010 ◽

Vol 13 (2) ◽

pp. 231 ◽

Cited By ~ 25

Author(s):

Haydar Çelik ◽

Emel Arinç

Keyword(s):

Dna Damage ◽

Cytochrome P450 ◽

Mitomycin C ◽

Dna Strand Breaks ◽

Protective Effects ◽

Cytochrome P450 Reductase ◽

Strand Breaks ◽

P450 Reductase ◽

Nadph Cytochrome P450 Reductase ◽

Dna Strand

PURPOSE. Idarubicin is a synthetic anthracycline anticancer drug widely used in the treatment of some hematological malignancies. The studies in our laboratory have clearly demonstrated that idarubicin can undergo reductive bioactivation by NADPH-cytochrome P450 reductase to free radicals with resulting formation of DNA strand breaks, which can potentially contribute to its genotoxic effects [Çelik, H., Arinç, E., Bioreduction of idarubicin and formation of ROS responsible for DNA cleavage by NADPH-cytochrome P450 reductase and its potential role in the antitumor effect. J Pharm Pharm Sci, 11(4):68-82, 2008]. In the current study, our aim was to investigate the possible protective effects of several phenolic antioxidants, quercetin, rutin, naringenin, resveratrol and trolox, against the DNA-damaging effect of idarubicin originating from its P450 reductase-catalyzed bioactivation. METHODS. DNA damage was measured by detecting single-strand breaks in plasmid pBR322 DNA using a cell-free agarose gel method. RESULTS. Our results indicated that, among the compounds tested, quercetin was the most potent antioxidant in preventing DNA damage. Quercetin significantly decreased the extent of DNA strand breaks in a dose-dependent manner; 100 μM of quercetin almost completely inhibited the DNA strand breakage. Unlike quercetin, its glycosidated conjugate rutin, failed to provide any significant protection against idarubicin-induced DNA strand breaks except at the highest concentration tested (2 mM). The protective effects of other antioxidants were significantly less than that of quercetin even at high concentrations. Quercetin was found to be also an effective protector against DNA damage induced by mitomycin C. CONCLUSION. We conclude that quercetin, one of the most abundant flavonoids in the human diet, is highly effective in reducing the DNA damage caused by the antitumor agents, idarubicin and mitomycin C, following bioactivation by P450 reductase.

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