Mechanisms of Formation, Genotoxicity, and Mutation of Guanine Oxidation Products

ArticleinChemical Research in Toxicology 19(4):491-505 · May 2006with24 Reads
Impact Factor: 3.53 · DOI: 10.1021/tx0600043 · Source: PubMed
    • "Due to its low redox potential, guanine (G) is the most vulnerable base. The oxidation of guanine results in formation of 8-oxo-7,8-dihydroguanine (8-oxoG), a cellular marker of oxidative stress [23]. When 8-oxoG assumes syn configuration, it is particularly mutagenic because it functionally mimics thymine. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: During Trypanosoma cruzi infection, macrophages produce reactive oxygen species (ROS) in a process called respiratory burst. Several works have aimed to elucidate the role of ROS during T. cruzi infection and the results obtained are sometimes contradictory. T. cruzi has a highly efficiently regulated antioxidant machinery to deal with the oxidative burst, but the parasite macromolecules, particularly DNA, may still suffer oxidative damage. Guanine (G) is the most vulnerable base and its oxidation results in formation of 8-oxoG, a cellular marker of oxidative stress. Methodology/principal findings: In order to investigate the contribution of ROS in T. cruzi survival and infection, we utilized mice deficient in the gp91phox (Phox KO) subunit of NADPH oxidase and parasites that overexpress the enzyme EcMutT (from Escherichia coli) or TcMTH (from T. cruzi), which is responsible for removing 8-oxo-dGTP from the nucleotide pool. The modified parasites presented enhanced replication inside murine inflammatory macrophages from C57BL/6 WT mice when compared with control parasites. Interestingly, when Phox KO macrophages were infected with these parasites, we observed a decreased number of all parasites when compared with macrophages from C57BL/6 WT. Scavengers for ROS also decreased parasite growth in WT macrophages. In addition, treatment of macrophages or parasites with hydrogen peroxide increased parasite replication in Phox KO mice and in vivo. Conclusions: Our results indicate a paradoxical role for ROS since modified parasites multiply better inside macrophages, but proliferation is significantly reduced when ROS is removed from the host cell. Our findings suggest that ROS can work like a signaling molecule, contributing to T. cruzi growth inside the cells.
    Full-text · Article · Apr 2016 · PLoS Neglected Tropical Diseases
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    • "[6] The guanine base in DNA, due to its low oxidation potential, is particularly sensitive , and a large number of guanine lesions have been characterized and studied in some detail. [7,8] One example is the 8-nitro-2 -deoxyguanosine, which is know to labilize the glycosidic bond causing the release of 8-nitroguanine, which can be detected in urine, and leaves an abasic site in DNA (Figure 1). [4,6,9] The synthesis and study of oligonucleotides containing site-specific DNA lesions lead to an understanding of how chemical changes of DNA generate specific mutations . "
    [Show abstract] [Hide abstract] ABSTRACT: The guanine base in DNA, due to its low oxidation potential, is particularly sensitive to chemical modifications. A large number of guanine lesions have been characterized and studied in some detail due to their relationship with tissue inflammations. Nevertheless, one example of these lesions is the formation of 8-nitro-guanosine, but the NMR data of this compound was only partially interpreted. A comprehensive study of the two possible tautomeric forms, through a detailed characterization of this compound, has implications for its base pairing properties. The target compound was obtained through a synthetic sequence of five steps, where all intermediates were fully characterized using spectral data. The analysis of the two tautomers was then evaluated through NMR spectroscopy and theoretical calculations of the chemical shifts and NH coupling constants, which were also compared with the data from guanosine.
    No preview · Article · Jan 2016 · Nucleosides Nucleotides & Nucleic Acids
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    • "Statistical significance is shown (*p % 0.05) using the untreated control at 60 min for determination. tential than any of the four normal bases, it can be further oxidized to more toxic products, including spiroiminodihydantoin and guanidinohydantoin (Neeley and Essigmann, 2006). Motivated by our nucleotide results and to test further the hypothesis that bactericidal antibiotics induce DSBs in the bacterial chromosome, we took advantage of a novel engineered fluorescent protein-based probe (Shee et al., 2013). "
    [Show abstract] [Hide abstract] ABSTRACT: Understanding how antibiotics impact bacterial metabolism may provide insight into their mechanisms of action and could lead to enhanced therapeutic methodologies. Here, we profiled the metabolome of Escherichia coli after treatment with three different classes of bactericidal antibiotics (?-lactams, aminoglycosides, quinolones). These treatments induced a similar set of metabolic changes after 30 min that then diverged into more distinct profiles at later time points. The most striking changes corresponded to elevated concentrations of central carbon metabolites, active breakdown of the nucleotide pool, reduced lipid levels, and evidence of an elevated redox state. We examined potential end-target consequences of these metabolic perturbations and found that antibiotic-treated cells exhibited cytotoxic changes indicative of oxidative stress, including higher levels of protein carbonylation, malondialdehyde adducts, nucleotide oxidation, and double-strand DNA breaks. This work shows that bactericidal antibiotics induce a complex set of metabolic changes that are correlated with the buildup of toxic metabolic by-products.
    Full-text · Article · Nov 2015 · Cell Reports
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