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

Abstract

Conjugation with glucuronic acid is a prevalent metabolic pathway of orally administrated curcumin, the bioactive diphenol of the spice turmeric. The major in vitro degradation reaction of curcumin is autoxidative transformation resulting in oxygenation and cyclization of the heptadienedione chain to form cyclopentadione derivatives. Here we show that curcumin-glucuronide is much more stable than curcumin, degrading about two orders of magnitude slower. Horseradish peroxidase-catalyzed oxidation of curcumin-glucuronide occurred at about 80% of the rate with curcumin, achieving efficient transformation. Using LC-MS and NMR analyses the major products of oxidative transformation were identified as glucuronidated bicyclopentadione diastereomers. Cleavage into vanillin-glucuronide accounted for about 10% of the products. Myeloperoxidase and lactoperoxidase oxidized curcumin-glucuronide whereas tyrosinase and xanthine oxidase were not active. Phorbol ester-activated primary human leukocytes showed increased oxidative transformation of curcumin-glucuronide which was inhibited by the peroxidase inhibitor sodium azide. These studies provide evidence that the glucuronide of curcumin is not an inert product and may undergo further enzymatic and non-enzymatic metabolism. Oxidative transformation by leukocyte myeloperoxidase may represent a novel metabolic pathway of curcumin and its glucuronide conjugate.

Effects of Curcumin on Tobacco Smoke-induced Hepatic MAPK Pathway Activation and Epithelial-Mesenchymal TransitionIn Vivo

“…Because of the potential clinical applications, the metabolism of curcumin has been studied extensively. The major metabolites of curcumin are curcumin glucuronide, curcumin sulfate, tetrahydrocurcumin, hexahydrocurcumin, vanillin and ferulic acid (Luis et al, ; Burapan et al, ; Jamil et al, ). Vanillin and ferulic acid showed greater overlap with the activities of curcumin (Luis et al, ).…”

“…The major metabolites of curcumin are curcumin glucuronide, curcumin sulfate, tetrahydrocurcumin, hexahydrocurcumin, vanillin and ferulic acid (Luis et al, ; Burapan et al, ; Jamil et al, ). Vanillin and ferulic acid showed greater overlap with the activities of curcumin (Luis et al, ). Tetrahydrocurcumin was active in colon carcinogenesis induced by azoxymethane, but biologically inert in the inhibition of COX‐2 in human colonic epithelial cells (Luis et al, ).…”

“…Vanillin and ferulic acid showed greater overlap with the activities of curcumin (Luis et al, ). Tetrahydrocurcumin was active in colon carcinogenesis induced by azoxymethane, but biologically inert in the inhibition of COX‐2 in human colonic epithelial cells (Luis et al, ). In vitro study found that curcumin glucuronide is less active in the inhibition of cancer cell growth and suppression of inflammatory mediators (Pal et al, ; Shoji et al, ).…”

The anti-inflammatory activity of curcumin is mediated by its oxidative metabolites

“…pounds by peroxidases (21,43), as well as inhibitory effects independent of oxidative activation, conceivably due to the enone moiety present in 2-12. Last, the autoxidation rate is only a surrogate, albeit quantitative, measure for formation and reactivity of the electrophiles with protein thiols.…”

Incomplete Hydrolysis of Curcumin Conjugates by β‐Glucuronidase: Detection of Complex Conjugates in Plasma

“…For one, not all conjugates formed in vivo may have been identified. In addition, direct analysis of phase‐II conjugates by liquid chromatography‐mass spectrometry (LC‐MS) faces technical challenges including incomplete recovery from the biological matrix (the conjugates are more polar than the polyphenols), “bad” chromatographic peak shapes (low signal‐to‐noise), inadvertent fragmentation during the ionization process in the mass spectrometer, and often a lack of suitable isotopic standards for quantification . Most of these problems are avoided when plasma metabolites are analyzed following hydrolysis of their phase‐II conjugates …”