title: Butylated hydroxyanisole specifically inhibits tumor necrosis factor-induced cytotoxicity and growth enhancement.
abstract: The effect of commonly used food antioxidants on recombinant tumor necrosis factor alpha (rTNF-alpha)-induced cytotoxicity, growth enhancement and adhesion has been evaluated. Butylated hydroxyanisole (BHA) and 4-hydroxymethyl-2,6-di-t-butylphenol (HBP) were the only two of nine antioxidants that completely inhibited rTNF-alpha-induced cytotoxicity in L929 and WEHI 164 fibrosarcoma cells. Ethoxyquin, propyl gallate and butylated hydroquinone only partially inhibited rTNF-alpha-induced cytotoxicity, while the antioxidants butylated hydroxytoluene (BHT), alpha-tocopherol, ascorbic acid and thiodipropionic acid had minimal effects. The only difference between the molecular structure of the efficient HBP and the non-efficient BHT, is a hydroxymethyl group instead of a hydroxyl group on the phenolic ring. Neither BHA nor BHT inhibited the activation of NF kappa B after 10 or 60 min challenge with rTNF-alpha in L929 cells. BHA also inhibited rTNF-alpha-induced, but not rIL-1 beta-induced growth enhancement in FS-4 fibroblasts. Further, BHA blocked both rTNF-alpha-induced and rIL-1 beta-induced prostaglandin E2 synthesis in FS-4 fibroblasts. BHA inhibited the rTNF-alpha-induced release of arachidonic acid in both FS-4 and L929 cells, suggesting that BHA inhibits cellular phospholipase(s). Neither alpha-tocopherol nor BHA inhibited rTNF-alpha-induced adhesiveness of human endothelial cells. The results indicate that BHA is a specific and potent inhibitor of rTNF-alpha- and rTNF-beta-induced cytotoxicity, as well as of rTNF-alpha-induced growth enhancement.
authors.affiliation: Department of Clinical Chemistry, Trondheim Regional Hospital, University of Norway.
authors.forename: O L
authors.initials: OL
authors.lastname: Brekke
authors.forename: M R
authors.initials: MR
authors.lastname: Shalaby
authors.forename: A
authors.initials: A
authors.lastname: Sundan
authors.forename: T
authors.initials: T
authors.lastname: Espevik
authors.forename: K S
authors.initials: KS
authors.lastname: Bjerve
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D001483:Base Sequence; D002083:Butylated Hydroxyanisole / Q000494:pharmacology*; D002084:Butylated Hydroxytoluene / Q000031:analogs & derivatives / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D015232:Dinoprostone / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D007375:Interleukin-1 / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D000975:Antioxidants; D007375:Interleukin-1; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D002084:Butylated Hydroxytoluene; D002083:Butylated Hydroxyanisole; D016718:Arachidonic Acid; C010915:2,6-di-tert-butyl-4-hydroxymethylphenol; D015232:Dinoprostone