MODULATION OF HISTAMINE-RELEASE FROM HUMAN BASOPHILS INVITRO BY PHYSIOLOGICAL CONCENTRATIONS OF ZINC

Abstract

Zn, at physiologic concentrations, inhibits in vitro histamine release from human basophils induced by several immunologic (i.e., antigen and anti-IgE) and nonimmunologic [Ca2+ ionophore A23187 [calcimycin] and formylated tripeptide formyl-methionyl-leucyl-phenylalanine (f-met peptide)] stimuli in a dose-dependent manner. Inhibition begins at .apprx. 10-6 (ionophore A23187, anti-IgE and antigen) or 10-5 M (f-met peptide) and is maximum at 10-4 M (80-100% inhibition of histamine release). The activity of Zn is .apprx. 25-fold greater with respect to ionophore A23187 (ID50 [median inhibitory dose] = 1.1 .times. 10-6 M) than to f-met peptide-induced (ID50 = 4 .times. 10-5 M) histamine release. Its activity on IgE-mediated histamine release is intermediate between the 2 extremes (ID50 = 9.7 .times. 10-4 M). Zn does not affect the first stage of histamine release but acts on the Ca-dependent 2nd stage. It is a competitive antagonist of the action of Ca2+ in histamine secretion induced by antigen, anti-IgE and f-met peptide (but not by A23187) with a Kd of .apprx. 1.2 .times. 10-5 M. The addition of colchicine with Zn fails to increase the inhibition due to the ion alone, suggesting the 2 compounds work a common mechanism of action. Deuterium oxide reversed dose-dependent manner, the inhibition of histamine release due to Zn. The effect of Zn on histamine release from human basophils may be related to its influence on the microtubule system, directly or via its interaction with Ca.