Metal-mediated DNA damage induced by curcumin in the presence of human cytochrome P450 isozymes.
Although curcumin is known to exhibit antitumor activity, carcinogenic properties have also been reported. To clarify the potentiality of carcinogenesis by curcumin, we have examined whether curcumin can induce DNA damage in the presence of cytochrome P450 (CYP) using [32P]-5(')-end-labeled DNA fragments obtained from genes relevant to human cancer. Curcumin treated with CYP 2D6, CYP1A1, or CYP1A2 induced DNA damage in the presence of Cu(II). CYP2D6-treated curcumin caused base damage, especially at 5(')-TG-3('), 5(')-GC-3('), and GG sequences. The DNA damage was inhibited by both catalase and bathocuproine, suggesting that reactive species derived from the reaction of H(2)O(2) with Cu(I) participate in DNA damage. Formation of 8-oxo-7,8-dihydro-2(')-deoxyguanosine was significantly increased by CYP2D6-treated curcumin in the presence of Cu(II). Time-of- flight mass spectrometry demonstrated that CYP2D6 catalyzed the conversion of curcumin to O-demethyl curcumin. Therefore, it is concluded that curcumin may exhibit carcinogenic potential through oxidative DNA damage by its metabolite.
Sakano
Katsuhisa
K
Department of Hygiene, Mie University School of Medicine, Mie 514-8507, Japan.
Kawanishi
Shosuke
S
D000818:Animals; D002273:Carcinogens / Q000009:adverse effects; D002374:Catalase / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002417:Cattle; D002614:Chelating Agents / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003474:Curcumin / Q000009:adverse effects*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000187:drug effects / Q000235:genetics; D019363:Cytochrome P-450 CYP1A1 / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects*; D003839:Deoxyadenosines / Q000032:analysis / Q000378:metabolism; D016166:Free Radical Scavengers / Q000378:metabolism / Q000494:pharmacology; D011905:Genes, ras; D006801:Humans; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism; D013058:Mass Spectrometry / Q000379:methods; D008670:Metals / Q000494:pharmacology*; D010618:Phenanthrolines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000235:genetics
D002273:Carcinogens; D002614:Chelating Agents; D019941:Cyclin-Dependent Kinase Inhibitor p16; D003839:Deoxyadenosines; D016166:Free Radical Scavengers; D007527:Isoenzymes; D008670:Metals; D010618:Phenanthrolines; D016159:Tumor Suppressor Protein p53; C078251:2'-deoxy-7,8-dihydro-8-oxoadenosine; D003577:Cytochrome P-450 Enzyme System; C002478:bathocuproine; D002374:Catalase; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D003474:Curcumin