title: Possible involvement of arachidonic acid metabolism in phenobarbital promotion of hepatocarcinogenesis.
abstract: The effects of inhibitors of arachidonic acid metabolism and antioxidants on the rat liver tumor promotion activity of phenobarbital (PB) were assessed using the enzyme-altered focus as the end-point lesion. Fischer 344 male rats were initiated with N-nitrosodiethylamine (200 mg/kg) and then divided into five groups placed on basal diet, diet containing 0.05% PB, diet containing 0.05% PB plus 0.75%, 1% or 1.5% levels of various inhibitors of arachidonic acid metabolism or antioxidants, or diet containing 1% or 1.5% inhibitors or antioxidants alone for 10 weeks, and then killed. p-Bromophenacyl bromide, an inhibitor of phospholipase A2, significantly inhibited the promotion activity of PB at dose levels of 0.75% and 1.5%, reaching plateau at 0.75%. Both quercetin, an inhibitor of lipoxygenase, and morin, a dual inhibitor of lipoxygenase-cyclooxygenase, significantly reduced the promotion activity of PB at the 1.5% but not 0.75% dose levels. Moreover, acetylsalicylic acid, an inhibitor of cyclooxygenase dose-dependently inhibited the promotion activity of PB. Among the antioxidants investigated, vitamin E did not affect, but n-propyl gallate and ethoxyquin exerted a dose-dependent inhibition of PB promotion. These results are strongly suggestive of an involvement of phospholipase A2, lipoxygenase and cyclooxygenase arachidonic acid metabolic pathways in the mechanisms underlying PB enhancement of hepatocarcinogenesis.
authors.affiliation: Department of Oncological Pathology, Nara Medical College, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Denda
authors.forename: H
authors.initials: H
authors.lastname: Ura
authors.forename: T
authors.initials: T
authors.lastname: Tsujiuchi
authors.forename: M
authors.initials: M
authors.lastname: Tsutsumi
authors.forename: H
authors.initials: H
authors.lastname: Eimoto
authors.forename: Y
authors.initials: Y
authors.lastname: Takashima
authors.forename: S
authors.initials: S
authors.lastname: Kitazawa
authors.forename: T
authors.initials: T
authors.lastname: Kinugasa
authors.forename: Y
authors.initials: Y
authors.lastname: Konishi
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D004052:Diethylnitrosamine / Q000633:toxicity*; D005015:Ethoxyquin / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010634:Phenobarbital / Q000494:pharmacology*; D011794:Quercetin / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D005723:gamma-Glutamyltransferase / Q000032:analysis; D047309:Flavones
chemical_list: D000098:Acetophenones; D016718:Arachidonic Acid; D001095:Arachidonic Acids; D014408:Biomarkers, Tumor; D004052:Diethylnitrosamine; D005015:Ethoxyquin; D005419:Flavonoids; D010634:Phenobarbital; D011794:Quercetin; D013755:Tetradecanoylphorbol Acetate; D005723:gamma-Glutamyltransferase; C008548:morin; D047309:Flavones; C006821:4-bromophenacyl bromide