title: Influence of glucuronidation and reduction modifications of resveratrol on its biological activities.
abstract: Resveratrol (3,5,4'-trihydroxystilbene, RES), a star among dietary polyphenols, shows a wide range of biological activities, but it is rapidly and extensively metabolized into its glucuronide and sulfate conjugates as well as to the corresponding reduced products. This begs the question of whether the metabolites of RES contribute to its in vivo biological activity. To explore this possibility, we synthesized its glucuronidation (3-GR and 4'-GR) and reduction (DHR) metabolites, and evaluated the effect of these structure modifications on biological activities, including binding ability with human serum albumin (HSA), antioxidant activity in homogeneous solutions and heterogeneous media, anti-inflammatory activity, and cytotoxicity against various cancer cell lines. We found that 1) 4'-GR, DHR and RES show nearly equal binding to HSA, mainly through hydrogen bonding, whereas 3-GR adopts a quite different orientation mode upon binding, thereby resulting in reduced ability; 2) 3-GR shows comparable (even equal) ability to RES in FRAP- and AAPH-induced DNA strand breakage assays; DHR, 3-GR, and 4'-GR exhibit anti-hemolysis activity comparable to that of RES; additionally, 3-GR and DHR retain some degree activity of the parent molecule in DPPH.-scavenging and cupric ion-initiated oxidation of LDL assays, respectively; 3) compared to RES, 4'-GR displays equipotent ability in the inhibition of COX-2, and DHR presents comparable activity in inhibiting NO production and growth of SMMC-7721 cells. Relative to RES, its glucuronidation and reduction metabolites showed equal, comparable, or some degree of activity in the above assays, depending on the specific compound and test model, which probably supports their roles in contributing to the in vivo biological activities of the parent molecule.
authors.affiliation: State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou 730000, China.
authors.forename: Dong-Liang
authors.initials: DL
authors.lastname: Lu
authors.forename: De-Jun
authors.initials: DJ
authors.lastname: Ding
authors.forename: Wen-Jing
authors.initials: WJ
authors.lastname: Yan
authors.forename: Ran-Ran
authors.initials: RR
authors.lastname: Li
authors.forename: Fang
authors.initials: F
authors.lastname: Dai
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.forename: Sha-Sha
authors.initials: SS
authors.lastname: Yu
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Xiao-Ling
authors.initials: XL
authors.lastname: Jin
authors.forename: Bo
authors.initials: B
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D020719:Glucuronides / Q000138:chemical synthesis / Q000737:chemistry*; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D051379:Mice; D062105:Molecular Docking Simulation; D010084:Oxidation-Reduction; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D000077185:Resveratrol; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism; D013267:Stilbenes / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D020719:Glucuronides; D012709:Serum Albumin; D013267:Stilbenes; D000077185:Resveratrol