title: 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.
authors.affiliation: Department of Pharmacology (Clinical Pharmacology) and Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical School, Nashville, TN 37232, USA.
authors.forename: Paula B
authors.initials: PB
authors.lastname: Luis
authors.affiliation: Department of Pharmacology (Clinical Pharmacology) and Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical School, Nashville, TN 37232, USA.
authors.forename: Odaine N
authors.initials: ON
authors.lastname: Gordon
authors.affiliation: Graduate School of Bioagricultural Sciences, Division of Biofunctional Chemistry, Nagoya University, Nagoya 464-8601, Japan.
authors.forename: Fumie
authors.initials: F
authors.lastname: Nakashima
authors.affiliation: Department of Pharmacology (Clinical Pharmacology) and Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical School, Nashville, TN 37232, USA.
authors.forename: Akil I
authors.initials: AI
authors.lastname: Joseph
authors.affiliation: Graduate School of Bioagricultural Sciences, Division of Biofunctional Chemistry, Nagoya University, Nagoya 464-8601, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Graduate School of Bioagricultural Sciences, Division of Biofunctional Chemistry, Nagoya University, Nagoya 464-8601, Japan; Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Uchida
authors.affiliation: Department of Pharmacology (Clinical Pharmacology) and Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical School, Nashville, TN 37232, USA. Electronic address: claus.schneider@vanderbilt.edu.
authors.forename: Claus
authors.initials: C
authors.lastname: Schneider
mesh_terms: D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003474:Curcumin / Q000378:metabolism*; D020719:Glucuronides / Q000378:metabolism*; D006801:Humans; D013058:Mass Spectrometry; D010084:Oxidation-Reduction; D010544:Peroxidases / Q000378:metabolism*; D066244:Proton Magnetic Resonance Spectroscopy
chemical_list: D020719:Glucuronides; D010544:Peroxidases; D003474:Curcumin
keywords: Autoxidation; Bicyclopentadione; Curcumin; Curcumin (PubChem CID: 969516); Curcumin-d6 (PubChem CID: 53464495); Curcumin-glucuronide (PubChem CID: 92024088); Glucuronide; Myeloperoxidase; Peroxidase