Distinct mechanisms of guanine-specific DNA photodamage induced by nalidixic acid and fluoroquinolone antibacterials

Fluoroquinolone antibacterials, which have been used for the treatment of a variety of infectious diseases, are reported to be photocarcinogenic. We i nvestigated the mechanisms of DNA damage by UVA radiation (365 nm) plus flu oroquinolone antibacterials using P-32-labeled DNA fragments obtained from the human c-Ha-ras-1 proto-oncogene and the p53 tumor suppressor gene. Phot ocarcinogenic nalidixic acid (NA), which is an old member of synthetic quin olone antibacterials, caused DNA damage specifically at 5'-GG-3' sequences, whereas lomefloxacin (LFLX) did not exhibit the site preference for consec utive guanines, LFLX-induced DNA photodamage was inhibited by sodium azide and enhanced in D2O, suggesting that singlet oxygen plays the key role in t he DNA damage. LFLX plus UVA induced the formation of 8-oxo-7,8-dihydro-2'- deoxyguanosine (8-oxodG) depending on LFLX concentrations, and 8-oxodG form ation was enhanced in single-stranded DNA. In contrast, NA induced larger a mounts of 8-oxodG in double-stranded DNA. ESR spin destruction method revea led that NA induced DNA photodamage through electron transfer but LFLX did not. These findings indicate that DNA damage induced by photoactivated LFLX and NA plays an important role in expression of their photocarcinogenicity , (C) 2000 Academic Press.