Peptide α-amidation: Differential regulation by disulfiram and its metabolite, diethyldithiocarbamate

• Published in: Neuropeptides (Edinburgh) Vol. 28; no. 6; pp. 333 - 340
• Main Authors: Mueller, G.P, Altarac, M
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.06.1995; Elsevier
• Subjects: Alcoholism and acute alcohol poisoning; Animals; Biological and medical sciences; Disulfiram - pharmacology; Ditiocarb - pharmacology; Heart Atria - drug effects; Heart Atria - enzymology; Male; Medical sciences; Mixed Function Oxygenases - antagonists & inhibitors; Mixed Function Oxygenases - metabolism; Multienzyme Complexes; Organ Specificity; Pituitary Gland - drug effects; Pituitary Gland - enzymology; Rats; Rats, Sprague-Dawley; Toxicology; Antialcohol drug; Peptides; Rat; Enzyme; Metabolite; Rodentia; Amidation; Vertebrata; Mammalia; Enzymatic activity; Animal; Peptidylglycine monooxygenase; Oxidoreductases; Mechanism of action
• ISSN: 0143-4179; 1532-2785
• DOI: 10.1016/0143-4179(95)90098-5

The rate limiting step in the α-amidation of bioactive peptides is catalyzed by peptidylglycine-α-hydroxylating mono-oxygenase (PHM; EC 1.14.17.3). Sustained treatment with disulfiram (Antabuse), the disulfide dimer of diethyldithiocarbamate (DDC), inhibits PHM in vivo, causing tissue levels of α-amidated peptides to decrease. As a compensatory response, PHM protein is modified in such a way that its activity is increased when assayed under optimal conditions in a test tube. Because disulfiram is rapidly reduced to DDC in vivo, this investigation sought to determine if metabolic transformation plays a role in the effects of disulfiram treatment on α-amidation. While disulfiram treatment reduced concentrations of α-amidated peptides in the pituitary neurointermediate lobe and brain, DDC treatment did not, even at comparatively high doses. Both treatments increased the activity of PHM extracted from the neurointermediate pituitary and assayed under optimal copper conditions in vitro. Only disulfiram treatment elicited an increase in PHM activity extracted from cardiac atrium. It is concluded that the activity of PHM is regulated in a tissue specific fashion and that not all of the actions of disulfiram require its metabolism to DDC.