Prooxidant action of furanone compounds: implication of reactive oxygen species in the metal-dependent strand breaks and the formation of 8-hydroxy-2'-deoxyguanosine in DNA.
Prooxidant properties of furanone compounds including 2,5-furanone (furaneol, 4-hydroxy-2,5-dimethyl-furan-3-one), 4,5-furanone (4,5-dimethyl-3-hydroxy-2(5H)-furanone) (sotolone) and cyclotene (2-hydroxy-3-methyl-2-cyclopenten-1-one) were analyzed in relation to the metal-reducing activity. Only 2.5-furanone known as a "strawberry or pineapple furanone" inactivated aconitase the most sensitive enzyme to active oxygen in the presence of ferrous sulfate, suggesting the furaneol/iron-mediated generation of reactive oxygen species. 2,5-Furanone caused strand scission of pBR322 DNA in the presence of copper. Treatment of calf thymus DNA with 2,5-furanone plus copper produced 8-hydroxy-2'-deoxyguanosine in DNA. 2,5-Furanone showed a potent copper-reducing activity, and thus, DNA strand breaks and the formation of 8-hydroxy-2'-deoxyguanosine by 2,5-furanone can be initiated by the production of superoxide radical through the reduction of cupric ion to cuprous ion, resulting in the conversion to hydrogen peroxide and hydroxyl radical. However, an isomer and analog of 2,5-furanone, 4,5-furanone and cyclotene, respectively, did not show an inactivation of aconitase, DNA injuries including strand breakage and the formation of 8-hydroxy-2'-deoxyguanosine, and copper-reducing activity. Cytotoxic effect of 2,5-furanone with hydroxyketone structure can be explained by its prooxidant properties: furaneol/transition metal complex generates reactive oxygen species causing the inactivation of aconitase and the formation of DNA base damage by hydroxyl radical.
Murakami
K
K
Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan.
Haneda
M
M
Makino
T
T
Yoshino
M
M
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000154:Aconitate Hydratase / Q000037:antagonists & inhibitors; D000818:Animals; D002417:Cattle; D003300:Copper / Q000494:pharmacology*; D003517:Cyclopentanes / Q000494:pharmacology; D018736:DNA Adducts / Q000138:chemical synthesis; D053960:DNA Breaks; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000096:biosynthesis; D005663:Furans / Q000494:pharmacology*; D016877:Oxidants / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000737:chemistry / Q000378:metabolism*
D003517:Cyclopentanes; D018736:DNA Adducts; D005663:Furans; D016877:Oxidants; D017382:Reactive Oxygen Species; C054511:4,5-dimethyl-3-hydroxy-2(5H)-furanone; C058427:furaneol; D003300:Copper; C028407:cyclotene; D000080242:8-Hydroxy-2'-Deoxyguanosine; D000154:Aconitate Hydratase; D003849:Deoxyguanosine