H3 receptor antagonist, thioperamide, inhibits adrenal steroidogenesis and histamine binding to adrenocortical microsomes and binds to cytochrome P450

• Published in: British journal of pharmacology Vol. 107; no. 1; pp. 161 - 164
• Main Authors: LaBella, F.S., Queen, G., Glavin, G., Durant, G., Stein, D., Brandes, L.J.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.09.1992; Nature Publishing
• Subjects: adrenal cortex; Adrenal Cortex - drug effects; Adrenal Cortex - metabolism; Adrenals. Interrenals; Adrenocortical hormones. Regulation; adrenocorticoids; Animals; Binding Sites; Biological and medical sciences; Cattle; Corticosterone - metabolism; Cytochrome P-450 Enzyme System - metabolism; cytochrome P450; Fundamental and applied biological sciences. Psychology; H3 antagonist; Histamine; Histamine - metabolism; Histamine Antagonists; histamine receptors; Hydrocortisone - metabolism; imidazoles; Male; Microsomes - metabolism; Piperidines - pharmacology; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; second messengers; Spectrophotometry, Ultraviolet; thioperamide; Vertebrates: endocrinology; Histaminergic receptor; H3 receptor; Endocrine gland; Adrenal glands; Cytochrome P450; Adrenal cortex; Microsome; Antihistaminic; In vitro; Histamine; In vivo; Biological fixation; Animal; Steroidogenesis
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1992.tb14480.x

1 Thioperamide (TP), an imidazole and a highly potent, specific antagonist of the histamine H3 receptor, inhibited the secretion of cortisol from bovine isolated adrenocortical cells (IC50 0.20 μm) 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 [3H]‐histamine (KD 27.7 μm) was potently inhibited by TP (Ki 0.33 μm). 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 μm and 1.5 mm for histamine, and 0.3 μm and 3.7 μm 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‐H3 intracellular site must be taken into account in studies designed to elucidate functional roles of H3 receptors.