title: Oxidative Transformation of Demethoxy- and Bisdemethoxycurcumin: Products, Mechanism of Formation, and Poisoning of Human Topoisomerase IIα.
abstract: Extracts from the rhizome of the turmeric plant are widely consumed as anti-inflammatory dietary supplements. Turmeric extract contains the three curcuminoids, curcumin (≈80% relative abundance), demethoxycurcumin (DMC; ≈15%), and bisdemethoxycurcumin (BDMC; ≈5%). A distinct feature of pure curcumin is its instability at physiological pH, resulting in rapid autoxidation to a bicyclopentadione within 10-15 min. Here, we describe oxidative transformation of turmeric extract, DMC, and BDMC and the identification of their oxidation products using LC-MS and NMR analyses. DMC autoxidized over the course of 24 h to the expected bicyclopentadione diastereomers. BDMC was resistant to autoxidation, and oxidative transformation required catalysis by horseradish peroxidase and H2O2 or potassium ferricyanide. The product of BDMC oxidation was a stable spiroepoxide that was equivalent to a reaction intermediate in the autoxidation of curcumin. The ability of DMC and BDMC to poison recombinant human topoisomerase IIα was significantly increased in the presence of potassium ferricyanide, indicating that oxidative transformation was required to achieve full DNA cleavage activity. DMC and BDMC are less prone to autoxidation than curcumin and contribute to the enhanced stability of turmeric extract at physiological pH. Their oxidative metabolites may contribute to the biological effects of turmeric extract.
authors: Departments of †Pharmacology (Clinical Pharmacology), ‡Biochemistry, and §Medicine (Hematology/Oncology), ||Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical School, Nashville, Tennessee 37232, United States.
authors: Odaine N
authors: ON
authors: Gordon
authors: Departments of †Pharmacology (Clinical Pharmacology), ‡Biochemistry, and §Medicine (Hematology/Oncology), ||Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical School, Nashville, Tennessee 37232, United States.
authors: Paula B
authors: PB
authors: Luis
authors: Departments of †Pharmacology (Clinical Pharmacology), ‡Biochemistry, and §Medicine (Hematology/Oncology), ||Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical School, Nashville, Tennessee 37232, United States.
authors: Rachel E
authors: RE
authors: Ashley
authors: Departments of †Pharmacology (Clinical Pharmacology), ‡Biochemistry, and §Medicine (Hematology/Oncology), ||Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical School, Nashville, Tennessee 37232, United States.
authors: Neil
authors: N
authors: Osheroff
authors: Departments of †Pharmacology (Clinical Pharmacology), ‡Biochemistry, and §Medicine (Hematology/Oncology), ||Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical School, Nashville, Tennessee 37232, United States.
authors: Claus
authors: C
authors: Schneider
mesh_terms: D000951:Antigens, Neoplasm / Q000737:chemistry / Q000378:metabolism*; D030024:Curcuma / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D003474:Curcumin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D053837:DNA Cleavage / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000737:chemistry / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D036381:Diarylheptanoids; D004852:Epoxy Compounds / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D010084:Oxidation-Reduction; D010936:Plant Extracts / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D036381:Diarylheptanoids; D004852:Epoxy Compounds; D010936:Plant Extracts; C034786:bisdemethoxycurcumin; C012596:turmeric extract; D004250:DNA Topoisomerases, Type II; D003474:Curcumin; C050229:demethoxycurcumin