title: Mechanisms and kinetics of human arylamine N-acetyltransferase 1 inhibition by disulfiram.
abstract: Disulfiram has been used for decades to treat alcoholism. Its therapeutic effect is thought to be mediated by the irreversible inhibition of aldehyde dehydrogenase. Recent reports have indicated new therapeutic uses of disulfiram, in particular in human cancers. Although the biochemical mechanisms that underlie these effects remain largely unknown, certain enzymes involved in cancer processes have been reported to be targeted by disulfiram. Arylamine N-acetyltransferase 1 (NAT1) is a xenobiotic-metabolizing enzyme that biotransforms aromatic amine drugs and carcinogens. In addition to its role in xenobiotic metabolism, several studies have suggested that NAT1 is involved in other physiological and/or pathological processes, such as folate metabolism or cancer progression. In this report, we provide evidence that human NAT1 is a new enzymatic target of disulfiram. We found that disulfiram at clinically relevant concentrations impairs the activity of endogenous NAT1 in human cancer cells. Further mechanistic and kinetic studies indicated that disulfiram reacts irreversibly with the active site cysteine residue of NAT1, leading to its rapid inhibition (IC50 = 3.3 +/- 0.1 microM and k(i) = 6 x 10(4) M(-1) x min(-1)).
authors: Université Paris Diderot-Paris 7, Unité de Biologie Fonctionnelle et Adaptative (BFA), CNRS Equipe d'Accueil Conventionée (EAC) 7059, Laboratoire des Réponses Moléculaires et Cellulaires aux Xénobiotiques, 75013, Paris, France.
authors: Florence
authors: F
authors: Malka
authors: Julien
authors: J
authors: Dairou
authors: Nilusha
authors: N
authors: Ragunathan
authors: Jean-Marie
authors: JM
authors: Dupret
authors: Fernando
authors: F
authors: Rodrigues-Lima
mesh_terms: D000427:Alcohol Deterrents / Q000494:pharmacology*; D001191:Arylamine N-Acetyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D003545:Cysteine / Q000378:metabolism; D004221:Disulfiram / Q000494:pharmacology*; D004789:Enzyme Activation; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007700:Kinetics; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000427:Alcohol Deterrents; D007527:Isoenzymes; D011994:Recombinant Proteins; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1; D003545:Cysteine; D004221:Disulfiram