title: 2-Hydroxymethyl-1-naphthol diacetate (TAC) suppresses the superoxide anion generation in rat neutrophils.
abstract: We have investigated the inhibitory effect of 2-hydroxymethyl-1-naphthol diacetate (TAC) on the respiratory burst of rat neutrophils and the underlying mechanism of action was also assessed in this study. TAC caused concentration-related inhibition of the formylmethionyl-leucyl-phenylalanine (fMLP) plus dihydrocytochalasin B (CB)- and phorbol 12-myristate 13-acetate (PMA)-induced superoxide anion (O2*-) generation (IC50 10.2+/-2.3 and 14.1+/-2.4 microM, respectively) and O2 consumption (IC50 9.6+/-2.9 and 13.3+/-2.7 microM, respectively) of neutrophils. TAC did not scavenge the generated O2*- during dihydroxyfumaric acid autoxidation. TAC inhibited both the transient elevation of [Ca2+]i in the presence or absence of [Ca2+]o (IC50 75.9+/-8.9 and 84.7+/-7.9 microM, respectively) and the generation of inositol trisphosphate (IP3) (IC50 72.0+/-9.7 microM) in response to fMLP. Cytosolic phospholipase C (PLC) activity was also reduced by TAC at a same range of concentrations. The PMA-induced PKC-beta associated to membrane was attenuated by TAC (about 80% inhibition at 30 microM). Upon exposure to fMLP, the cellular cyclic AMP level was decreased in neutrophils pretreated with TAC. TAC attenuated fMLP-induced phosphorylation of mitogen-activated protein kinase (MAPK) p42/44 (IC50 17.4+/-1.7 microM), but not p38. The cellular formation of phosphatidic acid (PA) and, in the presence of ethanol, phosphatidylethanol (PEt) induced by fMLP was inhibited by TAC in a concentration-dependent manner (IC50 25.4+/-2.4 and 25.9+/-1.4 microM, respectively). TAC had no effect on the O2*- generation of PMA-stimulated and arachidonic acid (AA)-stimulated NADPH oxidase preparations. However, TAC caused concentration-related decrease of the membrane associated p47phoX in PMA-stimulated neutrophils (about 80% inhibition at 30 microM). We conclude that inhibition by TAC of the neutrophil respiratory burst is probably attributable to the blockade of the p42/44 MAPK and phospholipase D (PLD) pathways, the membrane translocation of PKC, and to the failure in assembly of a functional NADPH oxidase complex. Blockade of the PLC pathway by TAC probably plays a minor role.
authors.affiliation: Department of Medical Research, Taichung Veterans General Hospital, Graduate Institute of Pharmaceutical Chemistry, China Medical College, Taiwan.
authors.forename: J P
authors.initials: JP
authors.lastname: Wang
authors.forename: L T
authors.initials: LT
authors.lastname: Tsao
authors.forename: A Y
authors.initials: AY
authors.lastname: Shen
authors.forename: S L
authors.initials: SL
authors.lastname: Raung
authors.forename: L C
authors.initials: LC
authors.lastname: Chang
mesh_terms: D000818:Animals; D002118:Calcium / Q000097:blood; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000097:blood; D002462:Cell Membrane / Q000201:enzymology; D000242:Cyclic AMP / Q000097:blood; D003571:Cytochalasin B / Q000031:analogs & derivatives / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009252:NADPH Dehydrogenase / Q000097:blood; D019255:NADPH Oxidases / Q000097:blood; D009284:Naphthols / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D010101:Oxygen Consumption / Q000187:drug effects; D010739:Phospholipase D / Q000097:blood; D010750:Phosphoproteins / Q000097:blood; D011493:Protein Kinase C / Q000097:blood; D051381:Rats; D016897:Respiratory Burst / Q000187:drug effects*; D013481:Superoxides / Q000097:blood*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: C119438:2-hydroxymethyl-1-naphthol diacetate; D009284:Naphthols; D010750:Phosphoproteins; D013481:Superoxides; C024794:dihydrocytochalasin B; D003571:Cytochalasin B; D009240:N-Formylmethionine Leucyl-Phenylalanine; D000242:Cyclic AMP; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D009252:NADPH Dehydrogenase; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010739:Phospholipase D; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium