Biochemical properties of anti-inflammatory drugs—VIII: Inhibition of histamine formation catalysed by substrate-specific mammalian histidine decarboxylases. Drug antagonism of aldehyde binding to protein amino groups

Abstract

Kinetic studies have shown that a number of acidic anti-inflammatory drugs (salicylate, “Ibufenac”, phenylbutazone, Indomethacin and Flufenamic acid) inhibit histamine formation by competing with pyridoxal phosphate for the coenzyme binding site, believed to be a lysyl ϵ-amino group on mammalian histidine decarboxylase. Apparent inhibitor constants ( Ki's) for these drugs were measured. These drugs also inhibited the binding of pyridoxal phosphate and 2,4,6-trinitro-benzaldehyde (TNBAL) to ϵ-amino groups of bovine plasma albumin at pH 7.5. A number of chemical analogues of these drugs were screened for their ability to (i) inhibit histamine formation in vitro and to (ii) retard the formation of the red coloration which forms when TNBAL reacts with albumin at pH 7.5 (and provides a novel colorimetric method for testing potential drug activity). Other compounds with notable drug activity in these two assays [(i) and (ii) above] include Sanochrysin, “Biogastrone”, pentachlorophenol and phenylindanedione—all of which, like the anti-inflammatory drugs named above, also uncouple oxidative phosphorylation.