Anti- and Pro-oxidant Effects of Oxidized Quercetin, Curcumin or Curcumin-related Compounds with Thiols or Ascorbate as Measured by the Induction Period Method

Abstract

Phenolic antioxidants, such as quercetin (QUE), curcumin (CUR) and the CUR-related compounds eugenol (EUG) and isoeugenol (IsoEUG), do not act in isolation in vivo but form an intricate antioxidant network together with ascorbate or glutathione (GSH). To clarify the antioxidant/prooxidant activity of these compounds in their interplay with ascorbate or GSH, the induction period (IP) and propagation rate (Rp) for mixtures of 2-mercapto-1-methylimidazole (MMI, a thiol) or L-ascorbyl-2,6-dibutyrate (ASDB, an ascorbate derivative) with QUE, CUR, EUG or IsoEUG were determined from differential scanning calorimetry (DSC) monitoring of the polymerization of methyl methacrylate (MMA), initiated by thermal decomposition of 1.0 mol% benzoyl peroxide (BPO, a PhCOO^. radical) under nearly anaerobic conditions. The IP (min) for 0.01 mol% test compounds declined in the order CUR (28.31) > IsoEUG (19.47) > EUG (16.83) > QUE (10.17) > MMI (2.06) > ASDB (0.16). The inhibition rate constant (k_inh, M^-1s^-1) declined in the order ASDB (7.85×10⁵) > MMI (5.99×10⁴) > QUE (1.21×10⁴) > EUG (7.93×10³) > IsoEUG (7.04×10³) > CUR (4.50×10³). The observed IP for MMI/QUE mixtures, particularly at molar ratios of 2:1 and 5:1, was significantly less than that for QUE alone as well as that calculated for MMI/QUE. The decrease in IP was similar to the observed IP in the control, suggesting the occurrence of oxygen uptake, possibly due to the formation of thiol RS radicals which, together with oxygen, produce oxo- and peroxo-sulphur radicals. The observed IPs for MMI/CUR or the MMI/IsoEUG mixtures, particularly the former, were less than the corresponding calculated IPs, suggesting co-oxidation of the MMI without oxygen uptake. In contrast, the observed IP of MMI/EUG mixtures was much greater than the corresponding calculated IP, suggesting the formation of an new antioxidative adduct between EUG-quinonemethide and MMI. The observed IP for the ASDB/QUE mixtures was greater than the corresponding calculated IP, suggesting the effectiveness of QUE as a co-antioxidant for ascorbate. In contrast, the observed IP for the ASDB/CUR mixtures was significantly less than the corresponding calculated IP, suggesting the catalytic effectiveness of CUR for ascorbate co-oxidation. Cancer cells are anaerobic in their metabolism and they selectively absorb more ascorbate than normal cells do. Thus, the present findings for the ASDB/CUR mixtures could help explain the effectiveness of CUR in chemoprevention by inducing cancer cell apoptosis. In addition, the findings for the MMI/QUE mixtures suggest the production of toxic oxo- and peroxo-sulphur radicals from thiols.