A Comparison of the Specificity of Inhibition by Phosphonate Esters of the First Component of Complement and the Antigen-Induced Release of Histamine From Guinea Pig Lung

Abstract

The ability of a number p-nitrophenylethyl alkyl, phenyl alkyl, chloroalkyl, and aminoalkyl phosphonates to inhibit the activated first component (C'1a) of guinea pig complement, and the antigen-induced release of histamine from sliced, perfused guinea pig lung has been compared. C'1a in its reactivity with these phosphonates is distinctly more similar to trypsin than to any of the other enzymes studied previously. It is suggested that both trypsin and C'1a possess an anionic group in the active center of the respective enzyme, but the distance between the anionic and esteratic site in C'1a might be less than in trypsin. The pattern of inhibition of histamine relase by the alkyl, phenyl alkyl, and chloroalkyl phosphonates is similar to the inhibition of C'1a by these compounds, although distinct differences are apparent. The aminoalkyl phosphonates are distinctly less active inhibitors of histamine release than the corresponding alkyl phosphonates, whereas the reverse is true of the inhibition of C'1a. On the basis of these differences, it is tentatively concluded that the organophosphorus-inhibitable enzymes in the guinea pig systems studied here are similar but not identical.

Mechanisms of the Inhibition of Chemotaxis by Phosphonate Esters

“…The esterase of the polymorphonuclear leukocyte activated by the chemotactic factor also differs from acetyl cholinesterase, chymotrypsiu, and trypsin (4,5). The inhibition profiles given by the reactions of the alkyl phosphonates, and the two aminoalkyl phosphonates with Ctla and the activatable enzyme of chemotaxis are essentially the same (4,6).…”

“…The inhibition profiles given by the reactions of the alkyl phosphonates, and the two aminoalkyl phosphonates with Ctla and the activatable enzyme of chemotaxis are essentially the same (4,6). However, the optimum activity against C'la in the chloroalkyl phosphonate series is reached by the 3-chloropropyl phosphonate, whereas the peak activity against the activatable enzyme of chemotaxis is given by the 4-chlorobutyl phosphonate (6).…”

“…Moreover, the results of substrate protection tests using the hexyl phosphonate showed that the inhibition obtained was due to the phosphonate, and not the impurity (9). The rabbit polymorphonuclear leukocyte is apparently similar to the sensitized guinea pig lung in not being susceptible to the action of the impurity (4).…”

“…However, the changes in reactivity of esterase with phosphonate structure are similar when the responses of the two biological systems to the chloroalkyl, alkyl, and aminoalkyl phosphonates are compared (4).…”

Antibodies Involved in Antigen-Induced Release of Slow Reacting Substance of Anaphylaxis (Srs-A) in the Guinea Pig and Rat

“…This interaction starts an enzymatic sequence leading to release of pharmacologically active substances from the sensitized ceils or a fluid phase substrate (1)(2)(3). These agents (histamine, serotonin, SRS-A, and kinins) in turn increase vascular permeability and/or constrict smooth muscles, contributing to a clinical phenomenon known as "anaphylaxis."…”