title: Peracetylation as a means of enhancing in vitro bioactivity and bioavailability of epigallocatechin-3-gallate.
abstract: (-)-Epigallocatechin-3-gallate (EGCG) is the widely studied catechin in green tea (Camellia sinensis). Previously, we have reported the low bioavailability of EGCG in rats and mice. As a means of improving the bioavailability of EGCG, we have prepared a peracetylated EGCG derivative (AcEGCG) and herein report its growth inhibitory activity and cellular uptake in vitro, as well as bioavailability in mice. AcEGCG exhibited enhanced growth inhibitory activity relative to EGCG in both KYSE150 human esophageal (IC50 = 10 versus 20 microM) and HCT116 human colon cancer cells (IC50 = 32 versus 45 microM). AcEGCG was rapidly converted to EGCG by HCT116 cells, and treatment of cells with AcEGCG resulted in a 2.8- to 30-fold greater intracellular concentration of EGCG as compared with treatment with EGCG. AcEGCG was also more potent than EGCG at inhibiting nitric oxide production (4.4-fold) and arachidonic acid release (2.0-fold) from lipopolysaccharide-stimulated RAW264.7 murine macrophages. Intragastric administration of AcEGCG to CF-1 mice resulted in higher bioavailability compared with administration of equimolar doses of EGCG. The plasma area under the curve from 0 to infinity (AUC0-->infinity) of total EGCG was 465.0 and 194.6 [(microg/ml) . min] from the administration of AcEGCG and EGCG, respectively. The t1/2 of EGCG was also increased following administration of AcEGCG compared with EGCG (441.0 versus 200.3 min). The AUC0-->infinity and t1/2 were also increased in small intestinal (2.8- and 4.3-fold, respectively) and colonic tissues (2.4- and 6.0-fold, respectively). These data suggest that acetylation represents a means of increasing the biological potency in vitro, increasing the bioavailability of EGCG in vivo, and may improve cancer-preventive activity.
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Lambert
authors.forename: Shengmin
authors.initials: S
authors.lastname: Sang
authors.forename: Jungil
authors.initials: J
authors.lastname: Hong
authors.forename: Seok-Joo
authors.initials: SJ
authors.lastname: Kwon
authors.forename: Mao-Jung
authors.initials: MJ
authors.lastname: Lee
authors.forename: Chi-Tang
authors.initials: CT
authors.lastname: Ho
authors.forename: Chung S
authors.initials: CS
authors.lastname: Yang
mesh_terms: D000085:Acetates / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000107:Acetylation; D000818:Animals; D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors; D001682:Biological Availability; D002392:Catechin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003106:Colon / Q000378:metabolism; D004950:Esterases / Q000378:metabolism; D006801:Humans; D007421:Intestine, Small / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009569:Nitric Oxide / Q000037:antagonists & inhibitors
chemical_list: D000085:Acetates; D016588:Anticarcinogenic Agents; C516941:peracetylated epigallocatechin-3-gallate; D016718:Arachidonic Acid; D009569:Nitric Oxide; D002392:Catechin; C045651:epigallocatechin gallate; D004950:Esterases