title: Pharmaceutical agents known to produce disulfiram-like reaction: effects on hepatic ethanol metabolism and brain monoamines.
abstract: Several pharmaceutical agents produce ethanol intolerance, which is often depicted as disulfiram-like reaction. As in the case with disulfiram, the underlying mechanism is believed to be the accumulation of acetaldehyde in the blood, due to inhibition of the hepatic aldehyde dehydrogenases. In the present study, chloramphenicol, furazolidone, metronidazole, and quinacrine, which are reported to produce a disulfiram-like reaction, as well as disulfiram, were administered to Wistar rats and the hepatic activities of alcohol and aldehyde dehydrogenases (1A1 and 2) were determined. The expression of aldehyde dehydrogenase 2 was further assessed by Western blot analysis, while the levels of brain monoamines were also analyzed. Finally, blood acetaldehyde was evaluated after ethanol administration in rats pretreated with disulfiram, chloramphenicol, or quinacrine. The activity of aldehyde dehydrogenase 2 was inhibited by disulfiram, chloramphenicol, and furazolidone, but not by metronidazole or quinacrine. In addition, although well known for metronidazole, quinacrine also did not increase blood acetaldehyde after ethanol administration. The protein expression of aldehyde dehydrogenase 2 was not affected at all. Interestingly, all substances used, except disulfiram, increased the levels of brain serotonin. According to our findings, metronidazole and quinacrine do not produce a typical disulfiram-like reaction, because they do not inhibit hepatic aldehyde dehydrogenase nor increase blood acetaldehyde. Moreover, all tested agents share the common property to enhance brain serotonin, whereas a respective effect of ethanol is well established. Therefore, the ethanol intolerance produced by these agents, either aldehyde dehydrogenase is inhibited or not, could be the result of a "toxic serotonin syndrome," as in the case of the concomitant use of serotonin-active medications.
authors.affiliation: Department of Pharmacology, Medical School, University of Ioannina, Ioannina, Greece. petros.karamanakos@kuh.fi
authors.forename: Petros N
authors.initials: PN
authors.lastname: Karamanakos
authors.forename: Periklis
authors.initials: P
authors.lastname: Pappas
authors.forename: Vassiliki A
authors.initials: VA
authors.lastname: Boumba
authors.forename: Christoforos
authors.initials: C
authors.lastname: Thomas
authors.forename: Michalis
authors.initials: M
authors.lastname: Malamas
authors.forename: Theodore
authors.initials: T
authors.lastname: Vougiouklakis
authors.forename: Marios
authors.initials: M
authors.lastname: Marselos
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000079:Acetaldehyde / Q000378:metabolism; D000426:Alcohol Dehydrogenase / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism*; D002701:Chloramphenicol / Q000008:administration & dosage / Q000494:pharmacology; D004221:Disulfiram / Q000008:administration & dosage / Q000494:pharmacology* / Q000592:standards; D004298:Dopamine / Q000378:metabolism; D004299:Dopamine beta-Hydroxylase / Q000037:antagonists & inhibitors; D000431:Ethanol / Q000378:metabolism*; D005664:Furazolidone / Q000008:administration & dosage / Q000494:pharmacology; D006719:Homovanillic Acid / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007031:Hypothalamus / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D007441:Intubation, Gastrointestinal; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008636:Mesencephalon / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008795:Metronidazole / Q000008:administration & dosage / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D011796:Quinacrine / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism
chemical_list: D015306:Biogenic Monoamines; D015102:3,4-Dihydroxyphenylacetic Acid; D008795:Metronidazole; D012701:Serotonin; D000431:Ethanol; D006897:Hydroxyindoleacetic Acid; D005664:Furazolidone; D002701:Chloramphenicol; D000426:Alcohol Dehydrogenase; D004299:Dopamine beta-Hydroxylase; D000444:Aldehyde Dehydrogenase; D000079:Acetaldehyde; D011796:Quinacrine; D004221:Disulfiram; D004298:Dopamine; D009638:Norepinephrine; D006719:Homovanillic Acid