title: Study of possible mechanisms involved in the inhibitory effects of coumarin derivatives on neutrophil activity.
abstract: To specify the site of action of the synthetic coumarin derivatives 7-hydroxy-3-(4'-hydroxyphenyl) coumarin (HHC) and 7-hydroxy-3-(4'-hydroxyphenyl) dihydrocoumarin (HHDC), we evaluated their effects on extra- and intracellular reactive oxygen species (ROS) formation in phorbol-myristate-13-acetate (PMA) stimulated human neutrophils. We studied also the effects of HHC and HHDC on possible molecular mechanisms which participate in the activation of NADPH oxidase, that is, on PKC activity, on phosphorylation of some PKC isoforms (α, βII, and δ), and on phosphorylation of the NADPH oxidase subunit p40(phox). Without affecting cytotoxicity, both coumarines tested were effective inhibitors/scavengers of ROS produced by neutrophils on extracellular level. HHC markedly diminished oxidant production and also, intracellularly, decreased PKC activity and partly phosphorylation of PKCα, βII. On the other hand, we did not observe any effect of coumarin derivatives on phosphorylation of PKC δ and on phosphorylation of the NADPH oxidase subunit p40(phox), which were suggested to be involved in the PMA-dependent intracellular activation process. In agreement with our previous findings, we assume that the different molecular structures of HHC and HHDC with their different physicochemical and free radical scavenging characteristics are responsible for their diverse effects on the parameters tested.
authors.affiliation: Institute of Experimental Pharmacology and Toxicology Slovak Academy of Sciences, Dúbravská cesta 9, 841 04 Bratislava, Slovakia.
authors.forename: Katarína
authors.initials: K
authors.lastname: Drábiková
authors.affiliation: Institute of Experimental Pharmacology and Toxicology Slovak Academy of Sciences, Dúbravská cesta 9, 841 04 Bratislava, Slovakia.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Perečko
authors.affiliation: Institute of Experimental Pharmacology and Toxicology Slovak Academy of Sciences, Dúbravská cesta 9, 841 04 Bratislava, Slovakia.
authors.forename: Radomír
authors.initials: R
authors.lastname: Nosál'
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v. v. i., Flemingovo náměsti 2, 161 10 Prague, Czech Republic.
authors.forename: Juraj
authors.initials: J
authors.lastname: Harmatha
authors.affiliation: Institute of Chemical Technology Prague, Technická 5, 166 28 Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Smidrkal
authors.affiliation: Institute of Experimental Pharmacology and Toxicology Slovak Academy of Sciences, Dúbravská cesta 9, 841 04 Bratislava, Slovakia.
authors.forename: Viera
authors.initials: V
authors.lastname: Jančinová
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D016923:Cell Death / Q000187:drug effects; D002474:Cell-Free System; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008163:Luminescent Measurements; D008297:Male; D008875:Middle Aged; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D055815:Young Adult
chemical_list: D003374:Coumarins; D007527:Isoenzymes; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; C085072:neutrophil cytosol factor 40K; D000255:Adenosine Triphosphate; C030123:coumarin; D013755:Tetradecanoylphorbol Acetate