Acrolein, an alpha,beta-Unsaturated Aldehyde, Irreversibly Inhibits the Acetylation of Aromatic Amine Xenobiotics by Human Arylamine N-Acetyltransferase 1

作者：Bui Linh C^*; Manaa Amine; Xu Ximing; Duval Romain; Busi Florent; Dupret Jean Marie; Rodrigues Lima Fernando; Dairou Julien

来源：Drug Metabolism and Disposition, 2013, 41(7): 1300-1305.

DOI：10.1124/dmd.113.052258

Acrolein is an electrophilic alpha,beta-unsaturated aldehyde of industrial, pharmaceutic, and toxicologic importance to which we are exposed in environmental, occupational, and therapeutic situations. Acrolein is known to exert different biologic 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.

• 出版日期2013-7