In vitro DNA modification by the ultimate carcinogen of 4-nitroquinoline-1-oxide: influence of superhelicity.
The effect of DNA tertiary structure on in vitro modification by 4-acetoxy-aminoquinoline-1-oxide (Ac-4-HAQO) was investigated. The reactivity of pAT153 plasmid DNA depended on the conformational state of the molecule: it progressively decreased according to the decrease of the superhelical tension, being negatively supercoiled DNA about two times more susceptible than singly-nicked relaxed DNA. HPLC of the three main Ac-4-HAQO adducts showed that 3-(deoxyguanosin-N2-yl)-4-aminoquinoline-1-oxide, N-(deoxyguanosin-C8-yl)-4-aminoquinoline-1-oxide and 3-(deoxyadenosin-N6-yl)-4-aminoquinoline-1-oxide accounted for 50, 25 and 10% of total quinoline DNA base adducts in all DNA conformations tested, except in the negatively supercoiled topoisomers where they accounted for 80, 15 and 5% respectively. DNA modification by Ac-4-HAQO resulted also in the formation of apurinic/apyrimidinic sites and in strand scissions. The quantification of these damages revealed that they represent an important fraction of all damaging events and that their yield is also influenced by DNA superstructure. Thus, these lesions must be considered as important DNA damage induced by Ac-4-HAQO.
Menichini
P
P
Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Fronza
G
G
Tornaletti
S
S
Galiègue-Zouitina
S
S
Bailleul
B
B
Loucheux-Lefebvre
M H
MH
Abbondandolo
A
A
Pedrini
A M
AM
D015112:4-Nitroquinoline-1-oxide / Q000378:metabolism / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004278:DNA, Superhelical / Q000187:drug effects; D006367:HeLa Cells / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D009600:Nitroquinolines / Q000494:pharmacology*; D009690:Nucleic Acid Conformation / Q000187:drug effects*; D010957:Plasmids / Q000187:drug effects
D004278:DNA, Superhelical; D009600:Nitroquinolines; D015112:4-Nitroquinoline-1-oxide; D004247:DNA; D004264:DNA Topoisomerases, Type I