Leukocyte-mediated inactivation of alpha 1-proteinase inhibitor is inhibited by amino analogues of alpha-tocopherol.
Human leukocytes stimulated by opsonized zymosan increase their NADPH oxidase-catalysed reduction of molecular oxygen. This leads to enhanced formation of superoxyl radicals and subsequently hydrogen peroxide. The leukocyte enzyme myeloperoxidase generates the strong microbicidal oxidant hypochlorite from hydrogen peroxide and chloride anions. Hypochlorite inactivates serum alpha 1-proteinase inhibitor, a protein which protects host tissue from digestion by proteinases, that are also secreted by stimulated leukocytes. Micromolar concentrations of a water-soluble, quaternary ammonium analogue of alpha-tocopherol (vitamin E) (3,4-dihydro-6-hydroxy-N,N,N-2,5,7,8-heptamethyl-2H-1-benzopyran-2 -ethanaminium 4-methylbenzenesulfonate) and its tertiary amine derivative (3,4-dihydro-2- (2-dimethylaminoethyl)-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol hydrochloride) were able to protect alpha 1-proteinase inhibitor from inactivation by stimulated human leukocytes. The mechanism of action of the quaternary ammonium analogue was further investigated. Selective inhibition of hydrogen peroxide formation is assumed to be the reason for its protective effect. This compound rapidly reacts with superoxyl radicals, but not with hydrogen peroxide, and is only a weak hypochlorite scavenger. It neither impedes exocytosis of elastase, nor effectively inhibits NADPH oxidase or myeloperoxidase. In contrast, superoxide dismutase, which enhances hydrogen peroxide formation, cannot protect alpha 1-proteinase inhibitor from inactivation.
Bolkenius
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FN
Marion Merrell Dow Research Institute, Strasbourg, France.
D005089:Exocytosis; D005949:Glucose Oxidase / Q000097:blood; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007962:Leukocytes / Q000201:enzymology / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000097:blood; D019255:NADPH Oxidases; D010196:Pancreatic Elastase / Q000097:blood; D009195:Peroxidase / Q000037:antagonists & inhibitors / Q000097:blood; D013481:Superoxides / Q000378:metabolism; D024505:Tocopherols; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000097:blood; D000515:alpha 1-Antitrypsin / Q000378:metabolism*
D000515:alpha 1-Antitrypsin; D013481:Superoxides; C067190:MDL 73404; C071522:3,4-dihydro-2-(2-dimethylaminoethyl)-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol; D014810:Vitamin E; D006861:Hydrogen Peroxide; D005949:Glucose Oxidase; D009195:Peroxidase; D014969:Xanthine Oxidase; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases; D010196:Pancreatic Elastase; D024505:Tocopherols