Human acetyltransferase polymorphisms.
Conjugation of primary amino and hydroxylamino groups with acetate, catalyzed by acetyl CoA-dependent arylamine acetyltransferase (NAT) enzymes, may play an important role in the intricate series of metabolic pathways that produce or prevent toxicity following exposure to homo- and heterocyclic arylamine and hydrazine xenobiotics. Two independently regulated and kinetically distinct human acetyltransferases are now known to exist, namely NAT1 and NAT2. Interindividual variation in NAT2 function is associated with the classical isoniazid acetylation polymorphism which was discovered over forty years ago. At last count, fifteen variant alleles at the NAT2 gene locus have been linked to the isoniazid 'acetylator phenotype', and each of these can be identified in population studies using specific PCR-based genotyping tests. On the other hand, NAT1 shows kinetic selectivity for compounds whose disposition is unrelated to the classical isoniazid acetylation polymorphism. NAT1 expression is also phenotypically variable in human populations, at least in part due to allelic differences at the NAT1 gene locus. Nine NAT1 variant alleles have been described to date, of which NAT1* 14 and NAT1* 15 clearly produce defective NAT1 proteins and lead to functional impairment in the metabolism of NAT1-selective substrates both in vivo and in vitro. On the other hand, it has been reported that the NAT1* 10 variant associates with elevated NAT1 activity and increased risk for cancers of the bladder and colon. Because of the important toxicologic consequences of allelic variation in NAT1 and NAT2 function for the metabolic activation of arylamine and heterocyclic amine procarcinogens, further studies are needed to improve our understanding of the extent of NAT allelic variation, to determine the functional capacity of each variant gene product, and to develop accurate methods of detecting them in population and epidemiological studies.
Grant
D M
DM
Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, Toronto, Ontario, Canada. grant@sickkids.on.ca
Hughes
N C
NC
Janezic
S A
SA
Goodfellow
G H
GH
Chen
H J
HJ
Gaedigk
A
A
Yu
V L
VL
Grewal
R
R
D000107:Acetylation; D000483:Alleles; D000588:Amines / Q000378:metabolism; D010131:Aminosalicylic Acid / Q000378:metabolism; D001191:Arylamine N-Acetyltransferase / Q000235:genetics* / Q000378:metabolism; D001711:Biotransformation; D005796:Genes; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D011110:Polymorphism, Genetic; D044469:Racial Groups
D000588:Amines; D007527:Isoenzymes; D010131:Aminosalicylic Acid; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human