PT  - JOURNAL ARTICLE
AU  - Linh C. Bui
AU  - Amine Manaa
AU  - Ximing Xu
AU  - Romain Duval
AU  - Florent Busi
AU  - Jean-Marie Dupret
AU  - Fernando Rodrigues Lima
AU  - Julien Dairou
TI  - Acrolein, an α, β-Unsaturated Aldehyde, Irreversibly Inhibits the Acetylation of Aromatic Amine Xenobiotics by Human Nat1
AID  - 10.1124/dmd.113.052258
DP  - 2013 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.113.052258
4099  - http://dmd.aspetjournals.org/content/early/2013/04/30/dmd.113.052258.short
4100  - http://dmd.aspetjournals.org/content/early/2013/04/30/dmd.113.052258.full
AB  - Acrolein is an electrophilic α, β-unsaturated aldehyde of industrial, pharmaceutical and toxicological importance to which we are exposed in environmental, occupational and therapeutic situations. Acrolein is known to exert different biological effects through reactions with cellular macromolecules such as DNA, certain proteins or glutathione. In many situations (such as in tobacco smoke or other fumes), exposure to acrolein occurs concomitantly with other compounds such as aromatic amine chemicals. Interestingly, it has been shown that acrolein could impact the cellular metabolism of aromatic xenobiotics through an indirect mechanism based on the transcriptional induction of phase II xenobiotic-metabolizing enzymes. Here we report a novel mechanism by which acrolein acts on the metabolism of aromatic foreign chemicals. We provide molecular, kinetic and cellular evidence that acrolein can react directly and irreversibly with arylamine N-acetyltransferases, a major family of xenobiotic-metabolizing enzymes involved in the metabolization of aromatic amine chemicals. Formation of an acrolein adduct with a catalytic cysteine residue in the active site is responsible for the impairment of aromatic amine acetylation by the enzyme. This biochemical process may represent an additional mechanism by which acrolein impacts the metabolism and fate of aromatic amine drugs and pollutants.