EFFECTS INVIVO AND INVITRO OF OXIDATIVE DAMAGE TO PURIFIED ALPHA-1-ANTITRYPSIN AND TO THE ENZYME-INHIBITING ACTIVITY OF PLASMA

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Abstract
The association of pulmonary emphysema with low blood concentrations of .alpha.1-antitrypsin is known. Other investigations showed that oxidizing agents can block the elastase-inhibitory activity of human .alpha.1-antitrypsin and that methionyl residues may play an important part in the mechanism of action of .alpha.1-antitrypsin. The kinetics of the interaction of purified chloramine T-treated .alpha.1-antitrypsin with porcine pancreatic elastase and trypsin were examined. Oxidized .alpha.1-antitrypsin did not inactivate elastase. The oxidized inhibitor could still slowly inactivate trypsin. Oxidation carried out in these studies converted methionyl residues in .alpha.1-antitrypsin to methionyl sulfoxide. The oxidized methionyl residue was apparently more critical to elastase inhibition than to trypsin inhibition and trypsin and elastase possibly bind to 2 different sites. The elastase inhibiting activities of rabbit, dog and monkey plasma were studied for susceptibility to inactivation by chloramine T. The rabbit has low blood concentrations of elastase-inhibiting activity that is relatively insensitive to oxidative damage. Monkey plasma closely resembles human plasma. I.v. infusion of a large dose of chloramine T into a Macaca arctoides monkey caused a decrease in elastase-inhibiting activity to unmeasurable values, with a concomitant slight increase in immunoreactive .alpha.1-antitrypsin. The animal reverted to full elastase inhibitory activity within 3.7 days. Toxic side effects of hemolytic anemia and methemoglobinemia were minimized by the administration of methylene blue. The apparent mild liver damage that might have occurred did not change albumin concentrations or prevent the liver from responding to stress by increasing blood concentrations of .alpha.1-antitrypsin.