Effects of phenacetin and its metabolite p-phenetidine on COX-1 and COX-2 activities and expression in vitro.
The present study was aimed to test the possible cyclooxygenase (COX)-1/COX-2 selectivity of the old analgesic drug phenacetin and its metabolite p-phenetidine, which exhibits high renal toxicity. Paracetamol (acetaminophen), the main metabolite of phenacetin with low renal toxicity, and indomethacin were selected as reference compounds. Collagen-stimulated platelet thromboxane B2 (TxB2) production and phorbol 12-myristate-13-acetate (PMA)-induced neutrophil prostaglandin E2 (PGE2) synthesis were used as indicators for COX-1 and COX-2 activity, respectively. Phenacetin was even less potent than paracetamol to reduce the production of both TxB2 and PGE2, and no clear preference for either of the COX-enzymes was seen. P-phenetidine was a more potent inhibitor, already at nanomolar level, of the synthesis of these prostanoids than indomethacin and showed some preference to COX-2 inhibition. Somewhat higher, micromolar, concentrations of p-phenetidine also reduced COX-2 expression in neutrophils. We suggest that the very potent inhibitory activity of p-phenetidine on PGE2 synthesis combined with the reduction of COX-2 expression could explain the renal papillary necrosis in phenacetin kidney.
Institute of Biomedicine, Pharmacology, University of Helsinki, Biomedicum, PO Box 63, 00014 University of Helsinki, Helsinki, Finland.
Esko
E
Kankuri
Erkka
E
Solatunturi
Heikki
H
Vapaatalo
D002478:Cells, Cultured; D003094:Collagen / Q000494:pharmacology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D006801:Humans; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000201:enzymology*; D008565:Membrane Proteins; D010615:Phenacetin / Q000494:pharmacology*; D010628:Phenetidine / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives* / Q000494:pharmacology; D013929:Thromboxane B2 / Q000378:metabolism
D007527:Isoenzymes; D008565:Membrane Proteins; D010628:Phenetidine; D013929:Thromboxane B2; C020922:4-O-methyl-12-O-tetradecanoylphorbol 13-acetate; D003094:Collagen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D010615:Phenacetin; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate