Rodent models of the human acetylation polymorphism: comparisons of recombinant acetyltransferases.
The acetylation polymorphism is associated with differential susceptibility to drug toxicity and cancers related to aromatic and heterocyclic amine exposures. N-Acetylation is catalyzed by two cytosolic N-acetyltransferases (NAT1 and NAT2) which detoxify many carcinogenic aromatic amines. NAT1 and NAT2 also activate (via O-acetylation) the N-hydroxy metabolites of aromatic and heterocyclic amine carcinogens to electrophilic intermediates which form DNA adducts and initiate cancer. The classical N-acetylation polymorphism is regulated at the NAT2 locus, which segregates individuals into rapid, intermediate, and slow acetylator phenotypes. Some human epidemiological studies associate slow acetylator and rapid acetylator phenotypes with increased susceptibility to urinary bladder and colorectal cancers, respectively. The acetylation polymorphism has been characterized in three rodent species (mouse, Syrian hamster, and rat) to test associations between NAT2 acetylator phenotype and susceptibility to aromatic and heterocyclic amine-induced cancers in various tumor target organs. NAT1 and NAT2 from rapid and slow acetylator mouse, Syrian hamster, and rat each have been cloned and sequenced. Recombinant NAT1 and NAT2 enzymes enzymes encoded by these genes have been characterized with respect to their catalytic activities for both activation (O-acetylation) and deactivation (N-acetylation) of aromatic and heterocyclic amine carcinogens. The acetylation polymorphisms in mouse, Syrian hamster, and rat are herein reviewed and compared as models of the human acetylation polymorphism.
Hein
D W
DW
Department of Pharmacology and Toxicology, University of North Dakota School of Medicine and Health Sciences, Grand Forks 58202-9037, USA. dhein@badlands.nodak.edu
Doll
M A
MA
Fretland
A J
AJ
Gray
K
K
Deitz
A C
AC
Feng
Y
Y
Jiang
W
W
Rustan
T D
TD
Satran
S L
SL
Wilkie
T R
TR
D000107:Acetylation; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000378:metabolism*; D006224:Cricetinae; D006358:Hot Temperature; D006801:Humans; D007536:Isomerism; D007700:Kinetics; D051379:Mice; D009153:Mutagens / Q000378:metabolism*; D011489:Protein Denaturation; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D013045:Species Specificity
D009153:Mutagens; D011994:Recombinant Proteins; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human