RODENT MODELS OF THE HUMAN ACETYLATION POLYMORPHISM - COMPARISONS OF RECOMBINANT ACETYLTRANSFERASES

The acetylation polymorphism is associated with differential susceptib ility to drug toxicity and cancers related to aromatic and heterocycli c amine exposures. N-Acetylation is catalyzed by two cytosolic N-acety ltransferases (NAT1 and NAT2) which detoxify many carcinogenic aromati c amines. NAT1 and NAT2 also activate (via O-acetylation) the N-hydrox y metabolites of aromatic and heterocyclic amine carcinogens to electr ophilic intermediates which form DNA adducts and initiate cancer. The classical N-acetylation polymorphism is regulated at the NAT2 locus, w hich segregates individuals into rapid, intermediate, and slow acetyla tor phenotypes. Some human epidemiological studies associate slow acet ylator and rapid acetylator phenotypes with increased susceptibility t o urinary bladder and colorectal cancers, respectively. The acetylatio n 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-induce d 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 encoded by these gene s have been characterized with respect to their catalytic activities f or both activation (O-acetylation) and deactivation (N-acetylation) of aromatic and heterocyclic amine carcinogens. The acetylation polymorp hisms in mouse, Syrian hamster, and rat are herein reviewed and compar ed as models of the human acetylation polymorphism.