Abstract
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 theN-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, andNat3* 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. IsoniazidN-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.
Footnotes
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Send reprint requests to: Gerald N. Levy, Department of Pharmacology, 1301 MSRBIII, 1150 W. Medical Center Drive, University of Michigan, Ann Arbor, MI 48109-0632.
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This work was supported by National Institute of Health grants GM 44965 and CA 39018.
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↵2 A consensus paper on nomenclature ofN-acetyltransferases (Vatsis et al., 1995) suggests the symbol NAT forN-acetyltransferase genes. However, the long-established style for mouse genes is to capitalize the first letter of the gene symbol followed by two lower case letters. We have followed the convention for the mouse; therefore, Nat is used.
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↵3 Preliminary report of four human variant alleles. Weber WW, de León JH, and Vatsis KP (1996)Pharmacogenetics: Bridging the Gap Between Basic Science and Clinical Application, IBC, Southborough, MA.
- Abbreviations used are::
- NAT
- N-acetyltransferase
- pABG
- p-aminobenzoylglutamate
- Received November 7, 1997.
- Accepted January 21, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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Substrate Selectivity of Mouse N-Acetyltransferases 1, 2, and 3 Expressed in COS-1 Cells
