title: Photolysis of sulfiram: a mechanism for its disulfiram-like reaction.
abstract: Sulfiram, a drug applied topically to treat scabies, produces effects similar to those of disulfiram after subsequent ingestion of ethanol. Disulfiram, used in aversion therapy in the treatment of alcoholism, inhibits hepatic aldehyde dehydrogenase (ALDH) causing an accumulation of acetaldehyde after ethanol ingestion. The increased tissue levels of acetaldehyde cause a spectrum of undesirable side-effects including flushing, nausea, vomiting, and tachycardia, which are referred to as the disulfiram reaction. Previous studies have shown that in vitro sulfiram is a very weak inhibitor of ALDH, but solutions of sulfiram markedly increase in potency with time. In the present study, fresh solutions of sulfiram were exposed to fluorescent room light under ambient conditions and analyzed at timed intervals by HPLC. At least eight products, including disulfiram, were formed in the light-exposed sulfiram solutions, but not in solutions kept in the dark. Structural characterization of two of the photolysis products was obtained by on-line microbore HPLC-mass spectrometry (mu LC-MS) and on-line microbore HPLC-tandem mass spectrometry (mu LC-MS/MS) using continuous flow-liquid secondary ion mass spectrometry (CF-LSIMS) as the primary ionization method. Sulfiram was converted to disulfiram at an initial rate of 0.7%/hr, and the formation of disulfiram correlated with the increase in ALDH inhibition in vitro. The results of this investigation show that while sulfiram is a weak inhibitor of ALDH in vitro, it is readily photoconverted to disulfiram, a very potent inhibitor of ALDH, which may explain the adverse reaction to ethanol after sulfiram therapy.
authors.affiliation: Department of Pharmacology, Mayo Medical School, Rochester, MN 55905.
authors.forename: D C
authors.initials: DC
authors.lastname: Mays
authors.forename: A N
authors.initials: AN
authors.lastname: Nelson
authors.forename: L M
authors.initials: LM
authors.lastname: Benson
authors.forename: K L
authors.initials: KL
authors.lastname: Johnson
authors.forename: S
authors.initials: S
authors.lastname: Naylor
authors.forename: J J
authors.initials: JJ
authors.lastname: Lipsky
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid / Q000379:methods; D004221:Disulfiram / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D008027:Light; D013058:Mass Spectrometry / Q000379:methods; D010782:Photolysis
chemical_list: C009822:monosulfiram; D000444:Aldehyde Dehydrogenase; D004221:Disulfiram