title: Human colorectal cancer cells efficiently conjugate the cyclopentenone prostaglandin, prostaglandin J(2), to glutathione.
abstract: Cyclopentenone prostaglandins (PGs), particularly those of the J-series, affect proliferation and differentiation in a number of cell lines. J-ring PGs have been shown to be ligands for the peroxisome proliferator-activated receptor (PPAR)-gamma and to modulate NF-kappaB-mediated gene transcription. We have previously reported that large quantities of eicosanoids, including PGJ(2), are produced by the human colorectal cancer cell line HCA-7 while lesser amounts of Delta(12)-PGJ(2) and 15-deoxy-Delta(12,14)-PGJ(2) are formed. In this and other cell lines, cyclopentenone PGs have been shown to increase cell proliferation, but factors that influence their formation and metabolism are poorly understood. Unlike other PGs, cyclopentenone PGs contain alpha,beta-unsaturated carbonyl groups that readily adduct various biomolecules such as glutathione (GSH) in vitro. We now report that in HCA-7 cells, PGJ(2) is largely metabolized by conjugation to GSH. Characterization of the adducts by liquid chromatography (LC)-mass spectrometry (MS) revealed two major metabolites consisting of (1) a novel GSH conjugate in which the carbonyl at C-11 of PGJ(2) is reduced and (2) intact PGJ(2) conjugated to GSH. Approximately 70% of the PGJ(2) added to HCA-7 cells was esterifed to GSH after 2 h of incubation, suggesting this pathway represents the major route of metabolic disposition of PGJ(2) in HCA-7 cells.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Cox
authors.forename: Laine J
authors.initials: LJ
authors.lastname: Murphey
authors.forename: William E
authors.initials: WE
authors.lastname: Zackert
authors.forename: Rebecca
authors.initials: R
authors.lastname: Chinery
authors.forename: Ramona
authors.initials: R
authors.lastname: Graves-Deal
authors.forename: Olivier
authors.initials: O
authors.lastname: Boutaud
authors.forename: John A
authors.initials: JA
authors.lastname: Oates
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Coffey
authors.forename: Jason D
authors.initials: JD
authors.lastname: Morrow
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002853:Chromatography, Liquid; D015179:Colorectal Neoplasms / Q000378:metabolism*; D003517:Cyclopentanes / Q000737:chemistry; D005978:Glutathione / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D013058:Mass Spectrometry; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D003517:Cyclopentanes; C007201:cyclopentanone; C037112:9-deoxy-delta-9-prostaglandin D2; D005978:Glutathione; D015230:Prostaglandin D2