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.

A Kinetic Degradation Study of Curcumin in Its Free Form and Loaded in Polymeric Micelles

“…Although not the main aim of this study the degradation of the log concentration versus time plot of demethoxycurcumin at pH=8.0 and 9.0, 37°C (Supplemental 8) yielded lower k obs (2.9 (±0.2) ×10 -3 and 30.4 (±2.5)×10 -3 h -1 ) than that of curcumin (7.6 (±0.4)×10 -3 and 76.0 (±0.4)×10 -3 h -1 ). This demonstrates that degradation rate of demethoxycurcumin is slower than that of curcumin, in line with literature data of Gordon et al (38). It should be mentioned that the peak areas of bisdemethoxycurcumin in the different chromatograms were too small for an accurate calculation of k obs .…”

“…These results demonstrate, as also reported previously, that pure curcumin particularly at low concentration is slightly more susceptible for oxidative degradation than that in its natural mixture. This can likely be ascribed to the stabilizing effect of the two derivative curcuminoids, bisdemethoxycurcumin and demethoxycurcumin as suggested by Gordon et al (38).…”

Degradation of Curcumin: From Mechanism to Biological Implications

“…32 The two methoxyphenol rings are required for the reaction but participate only indirectly by facilitating certain reaction steps without being changed (see below). 30 …”

“…30 There were, however, two important differences in the oxidation of DMC and BDMC compared with curcumin. First, the rate of autoxidation of DMC was markedly reduced such that its half life is in the range of hours rather than minutes (Table 1).…”

Investigation into experimental toxicological properties of plant protection products having a potential link to Parkinson's disease and childhood leukaemia†

“…Etoposide itself is converted via the catechol metabolite to etoposide 3-quinone, which is a covalent TopoII poison , whereas etoposide and its catechol are interfacial inhibitors. Curcumin is also an active TopoII poison due to its oxidised metabolites (Gordon et al, 2015). This fact deserves consideration if a screening for TopoII inhibition is envisaged.…”