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Quinolone dna adduct

Katie J Aldred, Adeline Payne, Olivia Voegerl
Quinolone antibacterials target the type II topoisomerases gyrase and topoisomerase IV and kill bacterial cells by converting these essential enzymes into cellular poisons. Although much is known regarding the interactions between these drugs and enzymes in purified systems, much less is known regarding their interactions in the cellular context due to the lack of a widely accessible assay that does not require expensive, specialized equipment. Thus, we developed an assay, based on the "rapid approach to DNA adduct recovery," or RADAR, assay that is used with cultured human cells, to measure cleavage complex levels induced by treating bacterial cultures with the quinolone ciprofloxacin...
February 27, 2019: Antibiotics
Peter Belenky, Jonathan D Ye, Caroline B M Porter, Nadia R Cohen, Michael A Lobritz, Thomas Ferrante, Saloni Jain, Benjamin J Korry, Eric G Schwarz, Graham C Walker, James J Collins
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...
November 3, 2015: Cell Reports
Xifeng Wu, Yun-Ling Zheng, T C Hsu
Risk assessment is now recognized as a multidisciplinary process, extending beyond the scope of traditional epidemiologic methodology to include biological evaluation of interindividual differences in carcinogenic susceptibility. Modulation of environmental exposures by host genetic factors may explain much of the observed interindividual variation in susceptibility to carcinogenesis. These genetic factors include, but are not limited to, carcinogen metabolism and DNA repair capacity. This chapter describes a standardized method for the functional assessment of mutagen sensitivity...
2014: Methods in Molecular Biology
Kallie M Stavros, Edward K Hawkins, Carmelo J Rizzo, Michael P Stone
2-Amino-3-methylimidazo[4,5-f]quinolone (IQ), a heterocyclic amine found in cooked meats, undergoes bioactivation to a nitrenium ion, which alkylates guanines at both the C8-dG and N2-dG positions. The conformation of a site-specific N2-dG-IQ adduct in an oligodeoxynucleotide duplex containing the iterated CG repeat restriction site of the NarI endonuclease has been determined. The IQ moiety intercalates, with the IQ H4a and CH3 protons facing the minor groove, and the IQ H7a, H8a and H9a protons facing the major groove...
March 2014: Nucleic Acids Research
Jakob Kljun, Ioannis Bratsos, Enzo Alessio, George Psomas, Urška Repnik, Miha Butinar, Boris Turk, Iztok Turel
Continuing the study of the physicochemical and biological properties of ruthenium-quinolone adducts, four novel complexes with the general formula [Ru([9]aneS3)(dmso-κS)(quinolonato-κ(2)O,O)](PF6), containing the quinolones levofloxacin (1), nalidixic acid (2), oxolinic acid (3), and cinoxacin (4), were prepared and characterized in solid state as well as in solution. Contrary to their organoruthenium analogues, these complexes are generally relatively stable in aqueous solution as substitution of the dimethylsulfoxide (dmso) ligand is slow and not quantitative, and a minor release of the quinolonato ligand is observed only in the case of 4...
August 5, 2013: Inorganic Chemistry
Mohan N Patel, Bhupesh S Bhatt, Promise A Dosi
The neutral mononuclear copper complexes with the quinolone antibacterial drug ciprofloxacin and bipyridine derivatives have been synthesized and characterized. Complexes were screened for their antibacterial activity against three Gram((-)) and two Gram((+)) bacteria, and study suggests inhibition of gyrase activity by metal complexes as the possible mechanism. The nucleolytic activity of adducts was carried out on double stranded pUC19 DNA using gel electrophoresis in the presence of radical scavenging agents that suggest hydrolytic cleavage mechanism for plasmid DNA...
April 2012: Applied Biochemistry and Biotechnology
Jakob Kljun, Anna K Bytzek, Wolfgang Kandioller, Caroline Bartel, Michael A Jakupec, Christian G Hartinger, Bernhard K Keppler, Iztok Turel
With the aim of exploring the anticancer properties of organometallic compounds with bioactive ligands, Ru(arene) compounds of the antibacterial quinolones nalidixic acid (2) and cinoxacin (3) were synthesized, and their physicochemical properties were compared to those of chlorido(η(6)-p-cymene)(ofloxacinato-κ(2)O,O)ruthenium(II) (1). All compounds undergo a rapid ligand exchange reaction from chlorido to aqua species. 2 and 3 are significantly more stable than 1 and undergo minor conversion to an unreactive [(cym)Ru(μ-OH)(3)Ru(cym)](+) species (cym = η(6)-p-cymene)...
May 9, 2011: Organometallics
Bavesh D Kana, Garth L Abrahams, Nackmoon Sung, Digby F Warner, Bhavna G Gordhan, Edith E Machowski, Liana Tsenova, James C Sacchettini, Neil G Stoker, Gilla Kaplan, Valerie Mizrahi
The environment encountered by Mycobacterium tuberculosis during infection is genotoxic. Most bacteria tolerate DNA damage by engaging specialized DNA polymerases that catalyze translesion synthesis (TLS) across sites of damage. M. tuberculosis possesses two putative members of the DinB class of Y-family DNA polymerases, DinB1 (Rv1537) and DinB2 (Rv3056); however, their role in damage tolerance, mutagenesis, and survival is unknown. Here, both dinB1 and dinB2 are shown to be expressed in vitro in a growth phase-dependent manner, with dinB2 levels 12- to 40-fold higher than those of dinB1...
April 2010: Journal of Bacteriology
María Eugenia Heres-Pulido, Irma Dueñas-García, Laura Castañeda-Partida, Luis Felipe Santos-Cruz, Viridiana Vega-Contreras, Rosa Rebollar-Vega, Juan Carlos Gómez-Luna, Angel Durán-Díaz
Broccoli (Brassica oleracea var. italica) has been defined as a cancer preventive food. Nevertheless, broccoli contains potentially genotoxic compounds as well. We performed the wing spot test of Drosophila melanogaster in treatments with organically grown broccoli (OGB) and co-treatments with the promutagen urethane (URE), the direct alkylating agent methyl methanesulfonate (MMS) and the carcinogen 4-nitroquinoline-1-oxide (4-NQO) in the standard (ST) and high bioactivation (HB) crosses with inducible and high levels of cytochrome P450s (CYPs), respectively...
January 2010: Food and Chemical Toxicology
J Robles, J Martín-Polo, L Alvarez-Valtierra, L Hinojosa, G Mendoza-Díaz
Theoretical electronic Structure methods have been employed to study the structure and activity of certain (free) quinolones and the interaction of their Cu(II)-complexes on a DNA model (Rhodamine 6G (rhod)). As a manner of assessing the generated geometries, the nalidixic acid geometrical parameters obtained were tested against the crystallographic ones and it was found that the average error in the calculated geometries is small. The present study allows us to (1) Rationalize the observed differences in antibiotic activities through their electronic hardnesses...
2000: Metal-based Drugs
Maria Cássia Ferreira de Aguiar, Daniela Gomes Dos Reis, Linaena Mericy da Silva Fonseca, Sérgio Vitorino Cardoso, Jackeline Alvarez Leite, Maria Auxiliadora Vieira do Carmo
OBJECTIVE: Metallothionein (MT) may play a preventive role in various carcinogenic process. 4NQO is an alkaline compound and potent mutagen that causes the formation of DNA adducts. The purpose of this study was to evaluate the immunoexpression of MT in palatal cells of mice submitted to the carcinogen 4NQO. STUDY DESIGN: C57BL/6 mice received applications of 4NQO to palate for periods of 8, 16, 20 and 24 weeks (experimental group). A control group received only applications of propylene glycol for the same periods...
July 2006: Medicina Oral, Patología Oral y Cirugía Bucal
Michael M Kim, Chad A Glazer, Elizabeth Mambo, Aditi Chatterjee, Ming Zhao, David Sidransky, Joseph A Califano
Constituents of tobacco can cause DNA adduct formation and are implicated in head and neck squamous cell cancer (HNSC) development. We investigated the capacity of HNSC cell lines to repair mitochondrial DNA (mtDNA) damage induced by a DNA adduct-forming agent. HNSC cell lines underwent 4-nitroquinoline 1-oxide (4NQO) exposure with subsequent rescue with normal media. Real-time quantitative PCR for nuclear DNA (nDNA) and mtDNA was performed. mtDNA to nDNA ratios were calculated and standardized to mock-treated cells to assess mtDNA repair ability...
February 2006: Oral Oncology
Cristina Marzano, Frazia Bettio, Adriana Chilin, Sergio Caffieri, Elena Reddi, Franco Bordin
The molecular structure of 1,4,6,8-tetramethylfuro[2,3-h]quinolin-2(1H)-one (FQ), a recent furocoumarin-like photosensitizer, has been modified with the aim of reducing its strong genotoxicity, by replacing the methyl group at 4 position with a hydroxymethyl one, and so obtaining 4-hydroxymethyl-1,6,8-trimethylfuro[2,3-h]quinolin-2(1H)-one (HOFQ). This modification gave rise to a strong reduction of lipophilicity and dark interaction with DNA. The formation of monoadducts (MA) was deeply affected, whereas the induction of bifunctional adducts between DNA and proteins (DPC(L>0)) was replaced by an efficient production of DNA-protein cross-links at zero length (DPC(L=0)), probably via guanine damage...
November 2005: Photochemistry and Photobiology
M Eugenia Heres-Pulido, Irma Dueñas-García, Laura Castañeda-Partida, Antonio Sánchez-García, Martha Contreras-Sousa, Angel Durán-Díaz, Ulrich Graf
Tamoxifen (TAM) is an anti-oestrogen used for treatment and prevention of human breast cancer, but it is also related to human endometrial and uterine cancer. The wing spot test in Drosophila melanogaster was employed to determine the genotoxic effects of TAM and 4-nitroquinoline-1-oxide (4-NQO), a carcinogen that produces adducts similar to TAM-DNA adducts detected in rodent liver and human liver microsomes. As Drosophila spp. have no oestrogen receptor, no effects can result in binding of TAM to a receptor...
May 2004: Mutagenesis
S Kawanishi, Y Hiraku
No abstract text is available yet for this article.
2001: Current Problems in Dermatology
R S Stern
A number of commonly used medications including quinolone antibiotics, psoralens and various tetracycline derivatives are photosensitizers. These chemicals enhance the erythema response to sunlight. The effect of such exposures on cancer risk has only been quantified in humans for oral psoralen photochemotherapy (PUVA). The experience of a cohort of 1380 patients followed for more than 20 years who received PUVA therapy for the treatment of psoriasis documents that long-term high dose exposure to PUVA greatly increases the risk of squamous cell carcinoma...
December 28, 1998: Toxicology Letters
A B Khodursky, N R Cozzarelli
Topoisomerase IV (Topo IV) is a mediator of quinolone toxicity in bacteria. In this work, we demonstrate that norfloxacin, a model quinolone, converts Escherichia coli Topo IV into a poisonous adduct on DNA as opposed to inhibiting topoisomerase activity. Norfloxacin inhibition of Topo IV induces a slow decline in DNA synthesis that parallels cell death. Treatment of cells with a lethal concentration of the antibacterial did not block chromosome segregation, the phenotype of catalytic inhibition of Topo IV...
October 16, 1998: Journal of Biological Chemistry
Q Li, D T Chu, A Claiborne, C S Cooper, C M Lee, K Raye, K B Berst, P Donner, W Wang, L Hasvold, A Fung, Z Ma, M Tufano, R Flamm, L L Shen, J Baranowski, A Nilius, J Alder, J Meulbroek, K Marsh, D Crowell, Y Hui, L Seif, L M Melcher, J J Plattner
Two novel series of 2-pyridones were synthesized by transposition of the nitrogen of 4-quinolones to the bridgehead position. This subtle interchange of the nitrogen atom with a carbon atom yielded two novel heterocyclic nuclei, pyrido[1,2-alpha]pyrimidine and quinolizine, which had not previously been evaluated as antibacterial agents and were found to be potent inhibitors of DNA gyrase. Quinolizines with a methyl group at the 9-position such as (S)-45a (ABT-719) demonstrate exceptional broad spectrum antibacterial activity...
August 2, 1996: Journal of Medicinal Chemistry
Y Naito, T Kumazawa, I Kino, O Suzuki
The effects of pyrroloquinoline quinone (PQQ) and PQQ-oxazole (PQQ-glycine adduct) on DNA synthesis were examined using cultured human fibroblasts. Confluent fibroblasts were cultured in serum-free Dulbecco's modified Eagle's media, and various concentrations of PQQ and PQQ-oxazole were added to the media. After incubation for 24 h, [3H]thymidine was added to the media as an indicator for DNA synthesis of the cells. The thymidine incorporation into the cells was significantly enhanced even in the presence of very low concentrations of PQQ (0...
1993: Life Sciences
C A McQueen, B M Way, S M Queener, G Schlüter, G M Williams
The genotoxicity of quinolone antibiotics has been evaluated in hepatocytes following in vitro and in vivo exposure. Unscheduled DNA synthesis (UDS) was induced in vitro in rat hepatocytes by norfloxacin, ofloxacin, pefloxacin, and ciprofloxacin but not by nalidixic acid. In vivo UDS was not observed in hepatocytes isolated 4 to 24 hr after exposure of adult male F344 rats to either a single dose (30 to 190 mg/kg) or repeated doses (40 mg/kg) of ciprofloxacin. Using the 32P-postlabeling technique, no modified bases were detected in hepatocytes exposed in vitro to ciprofloxacin...
November 1991: Toxicology and Applied Pharmacology
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