Analysis of Fluoroquinolone-mediated Photosensitization of 2′-Deoxyguanosine, Calf Thymus and Cellular DNA: Determination of Type-I, Type-II and Triplet–Triplet Energy Transfer Mechanism Contribution¶

Sauvaigo, Sylvie; Douki, Thierry; Odin, F.; Caillat, Sylvain; Ravanat, Jean‐Luc; Cadet, Jean

doi:10.1562/0031-8655(2001)073<0230:aofmpo>2.0.co;2

Cited by 87 publications

(102 citation statements)

References 44 publications

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“…These observations, which are in agreement with results obtained in CHO (28,30) and human skin cells (29), show that the mechanism of formation of CPDs upon UVA and UVB irradiation is different. The distribution of dimeric photoproducts suggests that a photosensitization reaction involving a triplet energy transfer mechanisms rather than a direct excitation process takes place upon exposure of skin to UVA, similarly to what is observed in the effects of some phototoxic drugs (49)(50)(51). Moreover, in contrast to a widely accepted hypothesis, we also found that, like in cultured cells (15,28,29), TϽϾT was produced in a larger amount than 8-oxodGuo in human skin exposed to UVA.…”

Section: Discussionsupporting

confidence: 67%

Cyclobutane pyrimidine dimers are predominant DNA lesions in whole human skin exposed to UVA radiation

Mouret

Baudouin

Charvéron

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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585

569

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Solar UV radiation is the most important environmental factor involved in the pathogenesis of skin cancers. The well known genotoxic properties of UVB radiation (290 -320 nm) mostly involve bipyrimidine DNA photoproducts. In contrast, the contribution of more-abundant UVA radiation (320 -400 nm) that are not directly absorbed by DNA remains poorly understood in skin. Using a highly accurate and quantitative assay based on HPLC coupled with tandem mass spectrometry, we determined the type and the yield of formation of DNA damage in whole human skin exposed to UVB or UVA. Cyclobutane pyrimidine dimers, a typical UVBinduced DNA damage, were found to be produced in significant yield also in whole human skin exposed to UVA through a mechanism different from that triggered by UVB. Moreover, the latter class of photoproducts is produced in a larger amount than 8-oxo-7,8-dihydro-2-deoxyguanosine, the most common oxidatively generated lesion, in human skin. Strikingly, the rate of removal of UVA-generated cyclobutane pyrimidine dimers was lower than those produced by UVB irradiation of skin. Finally, we compared the formation yields of DNA damage in whole skin with those determined in primary cultures of keratinocytes isolated from the same donors. We thus showed that human skin efficiently protects against UVB-induced DNA lesions, whereas very weak protection is afforded against UVA. These observations emphasize the likely role played by the UVA-induced DNA damage in skin carcinogenesis and should have consequences for photoprotection strategies.carcinogenesis ͉ DNA damage ͉ mutagenesis ͉ oxidative stress ͉ DNA repair O ccurrence of skin cancers, which mostly arise from exposure to solar UV radiation, has constantly increased in the recent years due to changes in life habits. Harmful effects of UV radiation are mostly associated with both direct and indirect photoinduced damage to DNA (1) that can lead to the induction of mutations. The chemical nature and the formation efficiency of the DNA lesions greatly depend on the wavelength of the incident photons. UVB radiation (290-320 nm), the most energetic mutagenic and carcinogenic component of solar radiation, is directly absorbed by DNA, giving rise to dimeric photoproducts between adjacent pyrimidine bases. Two types of these bulky modifications are produced, namely cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (1). Evidence for the involvement of these lesions in photocarcinogenesis is provided by the high proportion of p53 mutations (TC to TT or CC to TT transitions) detected at bipyrimidine sites in skin tumors (2-4).UVA radiation (320-400 nm), the other component of terrestrial UV radiation, is mutagenic in cultured cells (5, 6) and induces skin tumors in mice (7,8). In addition, UVA has been shown to be involved in immunosuppression (9) and is suspected to play a major role in the induction of melanoma (10, 11), the most severe type of skin cancers. Consequently, the carcinogenic properties of UVA have become a matter of concern...

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Section: Discussionsupporting

confidence: 67%

Cyclobutane pyrimidine dimers are predominant DNA lesions in whole human skin exposed to UVA radiation

Mouret

Baudouin

Charvéron

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

585

569

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“…Thus, T<>T formation is revealed by a specific repair enzyme: the T4 endonuclease V. Under the experimental conditions used and without enzymatic treatment, no single-strand breaks are photosensitized by NFX and ANFX. In agreement with previous observations based on HPLC-MS/MS analysis [17], NFX is able to photoinduce T<>T dimers as revealed by the detection of single-strand breaks after subsequent irradiation and enzymatic treatment (Fig. 4).…”

Section: Triplet-state Energy Of Thymine In Dna [27]supporting

confidence: 92%

“…Nevertheless, the ability of these drugs to induce DNA damage in the more complex environment characteristic of the whole cell, as well as the description of the modified bases and the possible molecular mechanisms involved in base alteration, have been less investigated. By contrast, fluoroquinolones have been shown to produce singleand double-strand breaks, as well as alkali-labile sites, by means of the comet assay [17,18].…”

Section: Photosensitization Of Cellular and Isolated Dna By 2-arylpromentioning

confidence: 99%

Drug-biomolecule interactions in the excited states

Lhiaubet‐Vallet

Miranda

2006

Pure and Applied Chemistry

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Drug-biomolecule interactions in the excited state are relevant from a photobiological point of view as they can be correlated with a number of photosensitization disorders such as photocarcinogenicity, photoallergy, phototoxicity, etc. Nonsteroidal antiinflammatory 2-arylpropionic acids and antibacterial fluoroquinolones have been selected as typical examples of photoactive drugs. Protein photosensitization has revealed photoadduct formation; the major amino acids involved are Tyr, Trp, and His. Generation of specific antibodies has allowed us to identify relevant structures of the drug epitopes. Then, drugs have been submitted to systematic steady-state and time-resolved studies on their photophysical properties, alone and in the presence of biomolecules: proteins, DNA, and their simple building blocks. The results are discussed in the framework of the chemical mechanisms underlying photosensitization by drugs and also in connection with the potential of drug excited states as (chiral) reporters for the binding sites of biomolecules.

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“…If true, thymine would be the main target because it has the lowest triplet state energy among all four DNA bases (48). Accordingly, sequence contexts of 5ЈTT, 5ЈTC, and 5ЈCT, respectively, are to be hit by UVA-derived triplet photosensitization reactions (49). In confirmation, most UVA1-induced CPDs along the p53 gene were formed at these sequence contexts, especially consequent to the highest irradiation dose.…”

Section: Discussionmentioning

confidence: 95%

DNA lesions induced by UV A1 and B radiation in human cells: Comparative analyses in the overall genome and in thep53tumor suppressor gene

Besaratinia

Synold

Chen

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

143

132

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The UV components of sunlight (UVA and UVB) are implicated in the etiology of human skin cancer. The underlying mechanism of action for UVB carcinogenicity is well defined; however, the mechanistic involvement of UVA in carcinogenesis is not fully delineated. We investigated the genotoxicity of UVA1 versus UVB in the overall genome and in the p53 tumor suppressor gene in normal human skin fibroblasts. Immuno-dot blot analysis identified the cis-syn cyclobutane pyrimidine-dimer (CPD) as a distinctive UVBinduced lesion and confirmed its formation in the genomic DNA of UVA1-irradiated cells dependent on radiation dose. HPLC͞tandem MS analysis showed an induction of 8-oxo-7,8-dihydro-2-deoxyguanosine in the genomic DNA of UVA1-irradiated cells only. Mapping of DNA damages by terminal transferase-dependent PCR revealed preferential, but not identical, formation of polymeraseblocking lesions and͞or strand breaks along exons 5-8 of the p53 gene in UVB-and UVA1-irradiated cells. The UVB-induced lesions detected by terminal transferase-PCR were almost exclusively mapped to pyrimidine-rich sequences; however, the UVA1-induced lesions were mapped to purine-and pyrimidine-containing sequences along the p53 gene. Cleavage assays with lesion-specific DNA repair enzymes coupled to ligation-mediated PCR showed preferential, but not identical, formation of CPDs along the p53 gene in UVB-and UVA1-irradiated cells. Additionally, dosedependent formation of oxidized and ring-opened purines and abasic sites was established in the p53 gene in only UVA1-irradiated cells. We conclude that UVA1 induces promutagenic CPDs and oxidative DNA damage at both the genomic and nucleotide resolution level in normal human skin fibroblasts. U ltraviolet (UV) irradiation from the sun is linked to basal and squamous cell carcinomas of the skin and cutaneous malignant melanoma in humans (1-3). The etiologically relevant UV wavelengths for development of these diseases are UVA (320-400 nm) and UVB (280-320 nm) (4, 5). UVA constitutes the major proportion of the solar UV reaching the surface of the Earth (Ϸ95%). The remaining fraction is the residual UVB, which is not absorbed by passage through the stratospheric ozone layer (6, 7). Biologically, however, UVB is a few orders of magnitude more potent than UVA in inducing photocarcinogenesis (8).The carcinogenic effect of UVB is irrefutably ascribed to its ability to produce promutagenic DNA lesions including cis-syn cyclobutane pyrimidine-dimers (CPDs) and to a lesser extent pyrimidine (6-4) pyrimidone photoproducts [(6-4)PPs]. The carcinogenicity of UVA is partly attributed to its mutagenicity; however, the mechanistic involvement of UVA in mutagenesis remains controversial. The latter is caused by the ambiguous DNA damaging effects of this wavelength (4, 5).Generally, the poor absorption of UVA by DNA supports the notion that UVA indirectly triggers mutagenesis via photosensitization reactions. Presumably, UVA sensitizes intracellular chromophores, thereby generating reactive oxygen species, which in tu...

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Analysis of Fluoroquinolone-mediated Photosensitization of 2′-Deoxyguanosine, Calf Thymus and Cellular DNA: Determination of Type-I, Type-II and Triplet–Triplet Energy Transfer Mechanism Contribution¶

Cited by 87 publications

References 44 publications

Cyclobutane pyrimidine dimers are predominant DNA lesions in whole human skin exposed to UVA radiation

Cyclobutane pyrimidine dimers are predominant DNA lesions in whole human skin exposed to UVA radiation

Drug-biomolecule interactions in the excited states

DNA lesions induced by UV A1 and B radiation in human cells: Comparative analyses in the overall genome and in thep53tumor suppressor gene

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