title: The phenytoin metabolite p-HPPH upregulates prostaglandin biosynthesis in human gingival fibroblasts challenged to interleukin-1.
abstract: The effects of and interactions between the major phenytoin (PHT) metabolite 5-parahydroxyphenyl-5-phenylhydantoin (p-HPPH) and interleukin-1 (IL-1 alpha, IL-1 beta) or tumor necrosis factor alpha (TNF alpha) on prostaglandin biosynthesis in human gingival fibroblasts were studied. IL-1 alpha, IL-1 beta and TNF alpha, dose-dependently, stimulated PGE2 formation in gingival fibroblasts. The metabolite, p-HPPH (1.2-2.4 micrograms/ml), did not induce PGE2 formation itself but potentiated IL-1 alpha and IL1 beta induced PGE2 formation in the gingival fibroblasts in a manner dependent on the concentration of both IL-1 and p-HPPH. The metabolite also stimulated IL-1 induced formation of 6-Keto PGF1 alpha, the stable breakdown product of PGI2, in a dose dependent manner. IL-1 beta induces release of [3H]-arachidonic acid ([3H]-AA) from prelabelled fibroblasts, which was potentiated by p-HPPH (> or = 1.2 micrograms/ml). TNF alpha (> or = 1 ng/ml) significantly stimulated the biosynthesis of PGE2 by a process that was also potentiated by p-HPPH. Addition of exogenous, unlabelled AA (10 microM) caused an increase of PGE2 formation in the fibroblasts that was not potentiated by p-HPPH (1.6 micrograms/ml). The results indicate that treatment with p-HPPH results in upregulation of prostaglandin synthesis in gingival fibroblasts challenged to IL-1 or TNF alpha at the level of phospholipase A2.
authors.affiliation: Department of Pedodontics, Faculty of Odontology, Karolinska Institutet, Huddinge, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Brunius
authors.forename: M
authors.initials: M
authors.lastname: Iinuma
authors.forename: I
authors.initials: I
authors.lastname: Andurén
authors.forename: U H
authors.initials: UH
authors.lastname: Lerner
authors.forename: T
authors.initials: T
authors.lastname: Modéer
mesh_terms: D002478:Cells, Cultured; D002648:Child; D004357:Drug Synergism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005881:Gingiva / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D008297:Male; D010672:Phenytoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011453:Prostaglandins / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D007375:Interleukin-1; D011453:Prostaglandins; D014409:Tumor Necrosis Factor-alpha; C001419:hydroxyphenytoin; D010672:Phenytoin