Journal article
Oxidation of 4-chlorobiphenyl metabolites to electrophilic species by prostaglandin H synthase
Chemical research in toxicology, Vol.22(1), pp.64-71
01/2009
DOI: 10.1021/tx800300t
PMCID: PMC2637223
PMID: 19105592
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′-, 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 di-substituted N-acetyl cysteine adducts. These studies clearly demonstrate that the phenolic metabolites of these environmental pollutants are activated by PGHS, as co-substrates, to highly reactive electrophilic PCB quinones, with a potential for protein and DNA damage, especially in non-hepatic tissues where the enzyme is found.
Details
- Title: Subtitle
- Oxidation of 4-chlorobiphenyl metabolites to electrophilic species by prostaglandin H synthase
- Creators
- Orarat Wangpradit - Institute of Life Sciences, Saxion University of Applied Sciences, Enschede, The NetherlandsLynn M Teesch - Institute of Life Sciences, Saxion University of Applied Sciences, Enschede, The NetherlandsS. V. Santhana Mariappan - Institute of Life Sciences, Saxion University of Applied Sciences, Enschede, The NetherlandsMichael W Duffel - Institute of Life Sciences, Saxion University of Applied Sciences, Enschede, The NetherlandsKarin Norstrom - Institute of Life Sciences, Saxion University of Applied Sciences, Enschede, The NetherlandsLarry W Robertson - Institute of Life Sciences, Saxion University of Applied Sciences, Enschede, The NetherlandsGregor Luthe - Institute of Life Sciences, Saxion University of Applied Sciences, Enschede, The Netherlands
- Resource Type
- Journal article
- Publication Details
- Chemical research in toxicology, Vol.22(1), pp.64-71
- DOI
- 10.1021/tx800300t
- PMID
- 19105592
- PMCID
- PMC2637223
- NLM abbreviation
- Chem Res Toxicol
- ISSN
- 0893-228X
- eISSN
- 1520-5010
- Language
- English
- Date published
- 01/2009
- Academic Unit
- Occupational and Environmental Health; Core Research Facilities; Pharmaceutical Sciences and Experimental Therapeutics; Iowa Superfund Research Program; Medicine Administration; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984002435302771
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