H-3 RECEPTOR ANTAGONIST, THIOPERAMIDE, INHIBITS ADRENAL STEROIDOGENESIS AND HISTAMINE BINDING TO ADRENOCORTICAL MICROSOMES AND BINDS TO CYTOCHROME-P450

1 Thioperamide (TP), an imidazole and a highly potent, specific antagonist of the histamine H-3 receptor, inhibited the secretion of cortisol from bovine isolated adrenocortical cells (IC50 0.20-mu-M) and, in the rat (5 mg kg-1) prevented both basal and stress-induced secretion of corticosterone. 2 In adrenocortical microsomes, low affinity binding of [H-3]-histamine (K(D) 27.7-mu-M) was potently inhibited by TP (K(i) 0.33-mu-M). 3 In adrenocortical microsomal membranes, both histamine and TP yielded type II difference absorption spectra, characteristic of the interaction between imidazole and cytochrome P450 enzymes. Dissociation constants for binding to P450, calculated from spectral data, were 15.9-mu-M and 1.5 mM for histamine, and 0.3-mu-M and 3.7-mu-M for TP. 4 In view of previously reported evidence for an intracellular mediator role of histamine in platelets, the present findings suggest a physiological role for histamine in the modulation of adrenal P450 monooxygenases that generate adrenocortical steroids. 5 The results suggest that direct adrenocortical inhibition by thioperamide at a non-H-3 intracellular site must be taken into account in studies designed to elucidate functional roles of H-3 receptors.