Comparison of HOCl traps with myeloperoxidase inhibitors in prevention of low density lipoprotein oxidation.
In this study, the production of the highly toxic oxidant hypochlorous acid (HOCl) by the phagocytic enzyme myeloperoxidase (MPO) was quantitated and the concomitant alterations of low density lipoprotein (LDL) were analyzed in view of the potential role of LDL in atherosclerosis. Using the monochlorodimedone assay, it was found that HOCl is produced in micromolar concentrations. The kinetics of the decrease of tryptophan fluorescence appeared to be a sensitive method to monitor LDL alterations under near in vivo conditions. Therefore, this method was used to subsequently compare the effectiveness of MPO inhibitors that block production of HOCl with compounds that act as HOCl traps. The efficiency of MPO inhibitors to prevent LDL damage increased in the series benzohydroxamic acid < salicylhydroxamic acid < 3-amino-1,2,4-triazole < sodium azide < potassium cyanide < p-hydroxy-benzoic acid hydrazide, while for the HOCl traps the protective efficiency increased in the series glycine < taurine < methionine. We conclude that HOCl traps may have high potential therapeutic impact in vivo due to their low toxicity, although high concentrations of them would have to reach sites of inflammation. In contrast, only low concentrations of a specific MPO inhibitor would be required to irreversibly inhibit the enzyme.
Jerlich
A
A
Institute of Molecular Biology, Biochemistry and Microbiology, University of Graz, Austria.
Fritz
G
G
Kharrazi
H
H
Hammel
M
M
Tschabuschnig
S
S
Glatter
O
O
Schaur
R J
RJ
D001161:Arteriosclerosis / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005453:Fluorescence; D005998:Glycine / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D062385:Hydroxybenzoates / Q000494:pharmacology; D006997:Hypochlorous Acid / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000737:chemistry* / Q000378:metabolism; D008715:Methionine / Q000494:pharmacology; D009504:Neutrophils / Q000201:enzymology / Q000378:metabolism; D009195:Peroxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011190:Potassium Cyanide / Q000494:pharmacology; D012457:Salicylamides / Q000494:pharmacology; D019810:Sodium Azide / Q000494:pharmacology; D013654:Taurine / Q000494:pharmacology; D014364:Tryptophan / Q000737:chemistry
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D062385:Hydroxybenzoates; D008077:Lipoproteins, LDL; D012457:Salicylamides; D013654:Taurine; C002429:4-hydroxybenzoic acid hydrazide; D006997:Hypochlorous Acid; D014364:Tryptophan; C005703:salicylhydroxamic acid; D019810:Sodium Azide; D008715:Methionine; D009195:Peroxidase; C006696:benzohydroxamic acid; D011190:Potassium Cyanide; D005998:Glycine