Activation of 2-aminofluorene by prostaglandin endoperoxide H synthase-2.
Prostaglandin endoperoxide H synthase is the key enzyme in the conversion of arachidonic acid to tissue prostanoids. Two isoforms of prostaglandin endoperoxide H synthase have been identified: PHS-1 is constitutively expressed in most tissues under normal physiological conditions and PHS-2 is expressed in response to inflammatory agents, tumor promotors, and other agents related to mitogenesis. Previous work demonstrated that PHS-1 can activate arylamine carcinogens. We report here that PHS-2 can also activate an arylamine carcinogen to form DNA adducts. This is shown by: (1) use of purified ovine PHS-2 to form DNA adducts; (2) increased DNA adduct formation, PHS-2 mRNA, and PHS-2 protein after treatment of HUVEC cells with the PHS-2 inducer PMA; and (3) transient expression of PHS-2 cDNA in COS-1 cells gave rise to both elevations of PHS-2 enzyme protein and DNA adduct formation. Finally, two PHS inhibitors, aspirin and indomethacin, showed significant inhibition of PHS-2-mediated DNA adduct formation.
Liu
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Department of Pharmacology, University of Michigan, Ann Arbor 48109-0632, USA.
Levy
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GN
Weber
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WW
D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D002273:Carcinogens / Q000378:metabolism*; D018736:DNA Adducts / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D005449:Fluorenes / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D010920:Placenta / Q000201:enzymology; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D012669:Seminal Vesicles / Q000201:enzymology; D012756:Sheep; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D014471:Umbilical Veins
D002273:Carcinogens; D018736:DNA Adducts; D018076:DNA, Complementary; D005449:Fluorenes; D007527:Isoenzymes; C012177:2-aminofluorene; D011451:Prostaglandin-Endoperoxide Synthases; D013755:Tetradecanoylphorbol Acetate; D001241:Aspirin; D007213:Indomethacin