tailieunhanh - Báo cáo khoa học: Mechanisms and kinetics of human arylamine N-acetyltransferase 1 inhibition by disulfiram

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 mech-anisms that underlie these effects remain largely unknown, certain enzymes involved in cancer processes have been reported to be targeted by disulfi-ram. | ễFEBS Journal Mechanisms and kinetics of human arylamine N-acetyltransferase 1 inhibition by disulfiram Florence Malka Julien Dairou Nilusha Ragunathan Jean-Marie Dupret and Fernando Rodrigues-Lima Université Paris Diderot-Paris 7 Unite de Biologie Fonctionnelle et Adaptative BFA CNRS Equipe d AccueilConventionee EAC 7059 Laboratoire des Reponses Moleculaires et Cellulaires aux Xenobiotiques 75013 Paris France Keywords arylamine N-acetyltransferase cancer drug target inhibition kinetics Correspondence F. Rodrigues-Lima Universite Paris Diderot-Paris 7 Unit of Functionaland Adaptative Biology BFA - CNRS EAC 7059 75013 Paris France Fax 33 1 57 27 83 29 Tel 33 1 57 27 83 32 E-mail Received 20 April2009 revised 28 May 2009 accepted 1 July 2009 doi 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 .