DNA damage induced by 4,6,8,9-tetramethyl-2H-furo[2,3-h]quinolin-2-one, a new furocoumarin analog: photochemical mechanisms.
Some photochemical and photobiological properties of 4,6,8,9-tetramethyl-2H-furo[2,3-h]quinolin-2-one (HFQ) were studied in comparison with its isomer 1,4,6,8-tetramethyl-2H-furo[2,3-h]quinolin-2-one (FQ) and 8-methoxypsoralen (8-MOP). The HFQ photobinds to DNA forming furan-side monoadducts (MAHFQ) that have molecular structure very similar to those of FQ (MAFQ). Unlike MA8-MOP and MAFQ, MAHFQ no longer photoreact. The HFQ, like FQ, produces moderate amounts of singlet oxygen but no superoxide anions. The HFQ and FQ induce numbers of DNA-protein cross-links (DPC), much more plentiful than those of 8-MOP (about two and seven times, respectively) but no interstrand cross-links. The mechanism of DPC formation was studied in vivo in mammalian cells by alkaline elution and in vitro using a new test mixing histones and DNA from calf thymus. The latter is a very useful technique for the double irradiation protocol. The DNA (or histones) are separately exposed to a first UVA dose in the presence of the sensitizer; then, after its unbound molecules have been removed, histones (or DNA) are added to assemble the chromatin-like complex that is irradiated again. According to in vitro and in vivo methods, DPC appear to be formed by FQ and 8-MOP by a biphotonic process that starts with monoadduct induction in DNA, followed by their conversion into DPC. In the resulting lesions, the sensitizer molecule forms a covalent bridge between the two macromolecules (DPC at length greater than zero). Instead, HFQ induces DPC by a monophotonic process; thus, HFQ is probably not a physical part of the bridge between DNA and proteins, which may be linked together directly, like DPC at zero length induced by UVC.
Bordin
F
F
Department of Pharmaceutical Chemistry, University of Padova, Italy. bordin@dsfarm.unipd.it
Baccichetti
F
F
Marzano
C
C
Carlassare
F
F
Miolo
G
G
Chilin
A
A
Guiotto
A
A
D000818:Animals; D002417:Cattle; D004249:DNA Damage; D066298:In Vitro Techniques; D008730:Methoxsalen / Q000633:toxicity; D010777:Photochemistry; D017319:Photosensitizing Agents / Q000633:toxicity*; D015363:Quinolones / Q000633:toxicity*; D017382:Reactive Oxygen Species; D014466:Ultraviolet Rays / Q000009:adverse effects
C101951:1,4,6,8-tetramethyl-2H-furo(2,3-h)quinolin-2-one; D017319:Photosensitizing Agents; D015363:Quinolones; D017382:Reactive Oxygen Species; C406865:4,6,8,9-tetramethyl-2H-furo(2,3-h)quinolin-2-one; D008730:Methoxsalen