Structure and regulation of the drug-metabolizing enzymes arylamine N-acetyltransferases.
Arylamine N-acetyltransferases (NAT) are xenobiotic-metabolizing enzymes responsible for N-acetylation of many arylamines. They are also important for O-acetylation of N-hydroxylated heterocyclic amines. These enzymes play thus an important role in the detoxification and activation of numerous therapeutic drugs and carcinogens. Two closely related polymorphic isoforms (NAT1 and NAT2) have been described in humans and interindividual variations in NAT genes have been shown to be a potential source of adverse drug reaction. In addition, NAT1 and/or NAT2 phenotypes may modulate the risk of certain cancers in people exposed to aromatic amine carcinogens. Recent advances on the regulation of human NAT1 activity has shown that hydroxylamine and/or nitroso intermediates of NAT1 substrates inhibit the enzyme through direct irreversible interaction with its catalytic cysteine residue. Oxidative molecules such as hydrogen peroxide, S-nitrosothiols and peroxynitrite have also been shown to inactivate reversibly or irreversibly the enzyme in a similar manner. In this review, after summarizing the general background on human NAT enzymes, we focus on the recent developments on the regulation of the activity of these drug-metabolizing enzymes by substrate-intermediates and by oxidant molecules. The recent findings reviewed here provide possible mechanisms by which these non genetic determinants inhibit NAT1 activity and thereby may affect drug efficacy/toxicity.
Dupret
Jean-Marie
JM
CNRS-UMR7000, Faculté de Médecine Pitié-Salpêtrière, 105 bd de l'Hôpital, 75013 Paris, France. mdupret@infobiogen.fr
Rodrigues-Lima
Fernando
F
D001191:Arylamine N-Acetyltransferase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D064420:Drug-Related Side Effects and Adverse Reactions; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000209:etiology; D018384:Oxidative Stress; D011110:Polymorphism, Genetic; D012306:Risk; D015262:Xenobiotics / Q000378:metabolism
D007527:Isoenzymes; D015262:Xenobiotics; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1; C478900:NAT2 protein, human