Cyanate-mediated inhibition of neutrophil myeloperoxidase activity.
Cyanate (CNO-) forms spontaneously in solutions containing urea, and is present in urine and the body fluids of uraemic patients. We have explored the possibility that CNO- might be one of the unknown substances responsible for the reported impairment, by urine and uraemic plasma, of neutrophil oxidative metabolism (especially as measured by luminol-enhanced chemiluminescence). Luminol-enhanced chemiluminescence generated by human neutrophils derives predominantly from the activity of myeloperoxidase (MPO) which produces hypochlorous acid from H2O2 and Cl-. We hypothesized that CNO- (which resembles the 'pseudohalide' thiocyanate, an alternative substrate for MPO) might somehow interfere with the activity of MPO. In support of this, we find: (i) CNO- inhibits both peroxidative and halogenating activities of MPO and also inhibits the enzyme within intact human neutrophils; (ii) the inhibition is H2O2-dependent, irreversible, accompanied by covalent addition of [14C]CNO- (or a carbon-containing fragment thereof) to the enzyme; (iii) CNO- also inhibits Cl-/H2O2/MPO-mediated bacterial killing. Impairment of this arm of neutrophil bactericidal activity by CNO- formed from urea may be one factor in the risk of urinary-tract infection associated with urinary stasis and perhaps in the generalized increase in susceptibility to infection in uraemic patients.
Qian
M
M
Department of Physiology and Cell Biology, Albany Medical College, New York, USA.
Eaton
J W
JW
Wolff
S P
SP
D001770:Blood Bactericidal Activity / Q000187:drug effects; D003485:Cyanates / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006997:Hypochlorous Acid / Q000037:antagonists & inhibitors; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology*; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000037:antagonists & inhibitors* / Q000097:blood*; D013211:Staphylococcus aureus / Q000187:drug effects
D003485:Cyanates; D006997:Hypochlorous Acid; D009195:Peroxidase