Mechanisms of inactivation of lipoxygenases by phenidone and BW755C.
Inhibition of soybean lipoxygenase (L-1) and potato 5-lipoxygenase (5-PLO) by the pyrazoline derivatives phenidone and BW755C only occurs after oxidation of these compounds by the peroxidase-like activity of the lipoxygenases. There is a clear relationship between this oxidation and the irreversible inactivation of L-1. The final product of phenidone oxidation by L-1, 4,5-didehydrophenidone, is not responsible of this inactivation, but the species derived from a one-electron oxidation of phenidone plays a key role in L-1 inactivation. In the absence of O2, inactivation of 1 mol of L-1 occurs after the oxidation of 34 mol of phenidone and the covalent binding of 0.8 mol of phenidone-derived metabolite(s) to L-1. In the presence of O2, inactivation of 1 mol of L-1 occurs already after oxidation of 11 mol of phenidone and only involves the covalent binding of 0.4 mol of phenidone-derived metabolite(s) to L-1. A mechanism is proposed for L-1 inactivation by phenidone, which involves the irreversible binding of a phenidone metabolite to the protein and the oxidation of an L-1 amino acid residue (in the presence of O2).
Cucurou
C
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Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (URA 400 CNRS), Paris, France.
Battioni
J P
JP
Thang
D C
DC
Nam
N H
NH
Mansuy
D
D
D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / Q000494:pharmacology; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine / Q000494:pharmacology*; D001094:Arachidonate 5-Lipoxygenase / Q000097:blood; D001205:Ascorbic Acid / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology; D004578:Electron Spin Resonance Spectroscopy; D004789:Enzyme Activation / Q000187:drug effects; D005290:Ferric Compounds / Q000737:chemistry; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000201:enzymology; D008084:Lipoxygenase / Q000737:chemistry; D016859:Lipoxygenase Inhibitors; D010084:Oxidation-Reduction; D010100:Oxygen / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology*; D011198:Solanum tuberosum / Q000201:enzymology; D013025:Glycine max / Q000201:enzymology; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000494:pharmacology
D005290:Ferric Compounds; D016859:Lipoxygenase Inhibitors; D011720:Pyrazoles; D013438:Sulfhydryl Compounds; D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D002374:Catalase; D008084:Lipoxygenase; D001094:Arachidonate 5-Lipoxygenase; D013482:Superoxide Dismutase; C015429:phenidone; D001205:Ascorbic Acid; D010100:Oxygen