Oxidative Metabolites of Curcumin Poison Human Type II Topoisomerases

Abstract

The polyphenol curcumin is the principal flavor and color component of the spice turmeric. Beyond its culinary uses, curcumin is believed to positively impact human health and displays antioxidant, anti-inflammatory, antibacterial, and chemopreventive properties. It also is in clinical trials as an anticancer agent. In aqueous solution at physiological pH, curcumin undergoes spontaneous autoxidation that is enhanced by oxidizing agents. The reaction proceeds through a series of quinone methide and other reactive intermediates to form a final dioxygenated bicyclopentadione product. Several naturally occurring polyphenols that can form quinones have been shown to act as topoisomerase II poisons (i.e., increase levels of topoisomerase II-mediated DNA cleavage). Because several of these compounds have chemopreventive properties, we determined the effects of curcumin, its oxidative metabolites, and structurally related degradation products (vanillin, ferulic acid, and feruloylmethane), on the DNA cleavage activities of human topoisomerase IIα and IIβ. Intermediates in the curcumin oxidation pathway increased DNA scission mediated by both enzymes ~4-5–fold. In contrast, curcumin and the bicyclopentadione, as well as vanillin, ferulic acid, and feruloylmethane, had no effect on DNA cleavage. As found for other quinone-based compounds, curcumin oxidation intermediates acted as redox-dependent (as opposed to interfacial) topoisomerase II poisons. Finally, under conditions that promote oxidation, the dietary spice turmeric enhanced topoisomerase II-mediated DNA cleavage. Thus, even within the more complex spice formulation, oxidized curcumin intermediates appear to function as topoisomerase II poisons.

Unraveling Curcumin Degradation

“…10, 11, and 12, or a later intermediate like spiroepoxide 6 are the active species responsible for the inactivation (poisoning) of human topoisomerase, rather than the parent curcumin or the final bicyclopentadione (26). Although not shown directly, it was inferred that electrophilic reaction intermediates form covalent adducts with cysteine residues in the topoisomerase active site that triggered DNA cleavage.…”

“…Topoisomerase poisoning is the therapeutic mechanism of many anticancer drugs in clinical use (24,25). Topoisomerase poisoning by curcumin required oxidative transformation to an active compound with short half-life (26). These studies indi-cated that unstable oxidative transformation products are an active principle rather than the parent curcumin.…”

Degradation of Curcumin: From Mechanism to Biological Implications

“…58-60 The requirement for oxidative transformation has clearly been shown for the topoisomerase poisoning activity of curcumin. 61 Neither dimethylcurcumin (which does not autoxidize; Table 1) nor reaction conditions that prevented autoxidation of curcumin resulted in poisoning of topoisomerase. The quinone methide intermediates were suggested as the electrophiles binding to active site cysteines, although the spiroepoxide could not be ruled out.…”

“…The quinone methide intermediates were suggested as the electrophiles binding to active site cysteines, although the spiroepoxide could not be ruled out. 61 …”

Oxidative metabolism of curcumin-glucuronide by peroxidases and isolated human leukocytes

“…Such has been suggested for the glucuronic acid conjugate (Fig. 1A) (6), for the reduced metabolites, especially tetra- and hexahydrocurcumin (7), for the degradation products formed via chain cleavage (vanillin, ferulic acid, and feruloylmethane) (8,9), and, lastly, for its oxidative metabolites, the formation of which has been recognized only recently (10–12). Few studies have tested the biological effects of curcumin-glucuronide in cell culture based assays, and these implied that the glucuronide is biologically inert or less active in the growth inhibition of cancer cells and suppression of inflammatory markers and cytokines (13,14).…”