title: Disulfiram and diethyldithiocarbamate are competitive inhibitors at the peripheral benzodiazepine receptor.
abstract: In the present study in vitro interactions of disulfiram (an agent used to induce ethanol intolerance in alcoholics), diethyldithiocarbamate (DDC), and metronidazole with central benzodiazepine receptors (CBR) and peripheral benzodiazepine (BZ) receptors (PBR) were investigated in rat tissues. Disulfiram displaced specific binding of [3H]PK 11195 from PBR in the cerebral cortex with an IC50 value of 5 x 10(-7) M. The binding of [3H]PK 11195 and [3H]Ro 5-4864 to PBR in the kidney was displaced by disulfiram with IC50 values of 7 x 10(-7) and 2 x 10(-7) M, respectively. DDC displaced [3H]PK 11195 binding to kidney membranes with an IC50 value of 5 x 10(-5) M. Binding of [3H] flunitrazepam to CBR in the cerebral cortex was not affected by either disulfiram or DDC. Metronidazole (up to 10(-4) M), a disulfiram congener, did not affect [3H]flunitrazepam (FNZ) and [3H] PK 11195 binding to CBR and PBR, respectively. Scatchard analysis of [3H]PK 11195 binding to kidney membranes, performed in the absence or presence of 7 x 10(-7) M disulfiram, decreased ligand affinity without influencing the maximal number of binding sites, suggesting a competitive inhibition. Beta-Mercaptoethanol (2 x 10(-2) M), which blocks the inhibitory activity of disulfiram and DDC at the acetaldehyde dehydrogenase, did not affect the inhibitory potency of disulfiram at the kidney PBR. Removal of disulfiram from kidney by repeated washing with Tris-HCl buffer resulted in the restoration of binding properties to control values, suggesting reversibility of disulfiram binding to PBR.
authors.affiliation: Department of Pharmacology, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa.
authors.forename: Y
authors.initials: Y
authors.lastname: Katz
authors.forename: R
authors.initials: R
authors.lastname: Weizman
authors.forename: A
authors.initials: A
authors.lastname: Weizman
authors.forename: M
authors.initials: M
authors.lastname: Gavish
mesh_terms: D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004221:Disulfiram / Q000378:metabolism / Q000494:pharmacology*; D004050:Ditiocarb / Q000378:metabolism / Q000494:pharmacology*; D005445:Flunitrazepam / Q000378:metabolism; D007546:Isoquinolines / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism
chemical_list: D007546:Isoquinolines; D011963:Receptors, GABA-A; D005445:Flunitrazepam; D004050:Ditiocarb; D004221:Disulfiram; C037850:PK 11195