CYANATE-MEDIATED INHIBITION OF NEUTROPHIL MYELOPEROXIDASE ACTIVITY

Cyanate (CNO-) forms spontaneously in solutions containing urea, and i s present in urine and the body fluids of uraemic patients, We have ex plored the possibility that CNO- might be one of the unknown substance s responsible for the reported impairment, by urine and uraemic plasma , of neutrophil oxidative metabolism (especially as measured by lumino l-enhanced chemiluminescence). Luminol-enhanced chemiluminescence gene rated by human neutrophils derives predominantly from the activity of myeloperoxidase (MPG) which produces hypochlorous acid from H2O2 and C l-. We hypothesized that CNO- (which resembles the 'pseudohalide' thio cyanate, an alternative substrate for MPO) might somehow interfere wit h 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 H2 O2-dependent, irreversible, accompanied by covalent addition of [C-14] CNO- (or a carbon-containing fragment thereof) to the enzyme; (iii) CN O- also inhibits Cl-/H2O2/MPO-mediated bacterial killing. Impairment o f this arm of neutrophil bactericidal activity by CNO- formed from ure a may be one factor in the risk of urinary-tract infection associated with urinary stasis and perhaps in the generalized increase in suscept ibility to infection in uraemic patients.