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Vol. 26, Issue 5, 502-505, May 1998
Department of Pharmacology Two human acetyl-CoA:arylamine N-acetyltransferases
(NAT1 and NAT2) have been identified. Therapeutic and carcinogenic
agents that are substrates for these isoenzymes (including isoniazid, sulfamethazine, p-aminobenzoic acid, 5-aminosalicyclic
acid, and 2-aminofluorene) have been used to evaluate the role of the
N-acetylation polymorphisms of NAT1 and NAT2 in the
treatment of disease and differential risk of various cancers among
individuals of differing acetylator phenotypes. The mouse is frequently
used as a model of the human acetylator polymorphism. As three Nat
isoenzymes have been identified in mouse, it is necessary to determine
the selectivity of mouse Nats toward common NAT substrates. In the present study, Nat1*, Nat2*8, and
Nat3* were expressed in COS-1 cells, and their substrate
selectivity was evaluated with various substrates. Under the conditions
used, mouse Nat2 had 20-, 2.4-, and 5.4-fold higher catalytic activity
for p-aminobenzoic acid, 5-aminosalicylic acid, and
2-aminofluorene, respectively, than Nat1. Isoniazid
N-acetylation was catalyzed only by mouse Nat1. For the
substrates tested in this study, mouse Nat3 exhibited activity only
toward 5-aminosalicylic acid and only at 1/20 the activity shown by
Nat2. In addition, p-aminobenzoylglutamate, the first
endogenous NAT substrate identified, was selective for mouse Nat2.
These results further support the functional analogy of mouse Nat2 and
human NAT1.
(L.E.-R., G.N.L., W.W.W.)
The
University of Michigan
Medical School
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