title: Peptide alpha-amidation: differential regulation by disulfiram and its metabolite, diethyldithiocarbamate.
abstract: The rate limiting step in the alpha-amidation of bioactive peptides is catalyzed by peptidylglycine-alpha-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 alpha-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 alpha-amidation. While disulfiram treatment reduced concentrations of alpha-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.
authors.affiliation: Department of Physiology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814-4799, USA.
authors.forename: G P
authors.initials: GP
authors.lastname: Mueller
authors.forename: M
authors.initials: M
authors.lastname: Altarac
mesh_terms: D000818:Animals; D004221:Disulfiram / Q000494:pharmacology*; D004050:Ditiocarb / Q000494:pharmacology*; D006325:Heart Atria / Q000187:drug effects / Q000201:enzymology; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009097:Multienzyme Complexes; D009928:Organ Specificity; D010902:Pituitary Gland / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D009097:Multienzyme Complexes; D004050:Ditiocarb; D006899:Mixed Function Oxygenases; C035189:peptidylglycine monooxygenase; D004221:Disulfiram