title: Oxidation of 4-chlorobiphenyl metabolites to electrophilic species by prostaglandin H synthase.
abstract: Hormonally sensitive tissues, like the prostate, ovary, and breast, increasingly studied as targets of environmental chemicals, are sources of an enzyme potentially capable of transforming and activating xenobiotics to highly reactive metabolites. Our study specifically addresses the question of whether prostaglandin H synthase (PGHS) can activate phenolic metabolites of polychlorinated biphenyls (PCBs). We found that human recombinant PGHS-2 catalyzed the oxidation of ortho (2',3'- and 3',4'-) and para (2',5'-) dihydroxy 4-chlorobiphenyl metabolites to their corresponding quinones. These were trapped in situ with N-acetyl cysteine, and the reaction products were isolated and characterized by liquid chromatography coupled mass spectrometry and (1)H and heteronuclear ((1)H-(13)C) nuclear magnetic resonance spectroscopy. Both mono- and di-N-acetyl cysteine Michael addition adducts were identified, with the 2',3'- and 2',5'-dihydroxy metabolites predominantly forming mono-N-acetyl cysteine adducts, while the 3',4'-dihydroxy predominantly formed disubstituted N-acetyl cysteine adducts. These studies clearly demonstrate that the phenolic metabolites of these environmental pollutants are activated by PGHS, as cosubstrates, to highly reactive electrophilic PCB quinones, with a potential for protein and DNA damage, especially in nonhepatic tissues where the enzyme is found.
authors.affiliation: Department of Occupational and Environmental Health, Interdisciplinary Graduate Program in Human Toxicology, College of Pharmacy, and Seamans Center for the Engineering Art and Sciences, University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Orarat
authors.initials: O
authors.lastname: Wangpradit
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Teesch
authors.forename: S V Santhana
authors.initials: SV
authors.lastname: Mariappan
authors.forename: Michael W
authors.initials: MW
authors.lastname: Duffel
authors.forename: Karin
authors.initials: K
authors.lastname: Norstrom
authors.forename: Larry W
authors.initials: LW
authors.lastname: Robertson
authors.forename: Gregor
authors.initials: G
authors.lastname: Luthe
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000737:chemistry; D001713:Biphenyl Compounds / Q000737:chemistry* / Q000633:toxicity; D002853:Chromatography, Liquid; D004249:DNA Damage; D004785:Environmental Pollutants / Q000737:chemistry* / Q000633:toxicity; D013058:Mass Spectrometry; D010084:Oxidation-Reduction; D011078:Polychlorinated Biphenyls / Q000737:chemistry / Q000633:toxicity; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011809:Quinones / Q000737:chemistry
chemical_list: D001713:Biphenyl Compounds; D004785:Environmental Pollutants; D011809:Quinones; D011078:Polychlorinated Biphenyls; D011451:Prostaglandin-Endoperoxide Synthases; C006983:4-chlorobiphenyl; D000111:Acetylcysteine