Prooxidant action of xanthurenic acid and quinoline compounds: role of transition metals in the generation of reactive oxygen species and enhanced formation of 8-hydroxy-2'-deoxyguanosine in DNA.
Xanthurenic acid, a product of tryptophan-NAD pathway, and quinoline compounds produced reactive oxygen species as a complex with iron. Aconitase, the most sensitive enzyme to oxidative stress was inactivated effectively by xanthurenic acid and to a lesser extent by 8-quinolinol in the presence of ferrous sulfate. The inactivation of aconitase was iron-dependent, and was prevented by TEMPOL, a scavenger of reactive oxygen species, suggesting that reduced iron bound to xanthurenic acid or 8-quinolinol can activate oxygen molecule to form superoxide radical. However, kynurenic acid and quinaldic acid without 8-hydroxyl group did not produce reactive oxygen species. Of the quinoline compounds tested, xanthurenic acid and 8-quinolinol with 8-hydroxyl group stimulated the autooxidation of ferrous ion, but kynurenic acid and quinaldic acid did not affect the oxidation of ferrous ion. Hydroxyl group at 8-positions of quinoline compounds was essential for the binding of iron causing the generation of reactive oxygen species. 8-Quinolinol effectively enhanced the ascorbate/copper-mediated formation of 8-hydroxy-2'-deoxyguanosine in DNA, suggesting the quinolinol/copper-dependent stimulation hydroxyl radical formation. Xanthurenic acid and 8-quinolinol as the metal-chelate complexes can show various cytotoxic effects by generating reactive oxygen species through the ferrous or cuprous ion-dependent activation of oxygen molecule.
Murakami
Keiko
K
Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Aichi, 480-1195, Japan.
Haneda
Miyako
M
Yoshino
Masataka
M
D000154:Aconitate Hydratase / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005296:Ferrous Compounds / Q000378:metabolism; D008670:Metals / Q000378:metabolism*; D015394:Molecular Structure; D010084:Oxidation-Reduction / Q000187:drug effects; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D014977:Xanthurenates / Q000494:pharmacology*
D005296:Ferrous Compounds; D008670:Metals; D011804:Quinolines; D017382:Reactive Oxygen Species; D014977:Xanthurenates; C028330:xanthurenic acid; D004247:DNA; C037219:quinoline; C055686:glyceraldehyde 3-phosphate phosphatase; D010744:Phosphoric Monoester Hydrolases; D000154:Aconitate Hydratase