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© 1994 Oxford University Press

OTHER

Molecular genetics of human polymorphic N-acetyltransferase: enzymatic analysis of 15 recombinant wild-type, mutant, and chimeric NAT2 allozymes

David W. Heln*, Ronald J. Ferguson, Mark A. Doll, Timothy D. Rustan and Kevin Gray

Department of Pharmacology and Toxicology, University of North Dakota School of Medicine, Grand Forks, ND 58202-9037 USA

* To whom correspondence should be addres

Received January 7, 1994; Accepted March 9, 1994

Human polymorphic W-acetyltransferase (NAT2) catalyzes the W-acetylatlon of arylamlne drugs and carcinogens. Human acetylator phenotype is regulated at the NAT2 locus and has been associated with differential risk to certain drug toxicities or cancer. We examined arylamlne substrate and acetyl coenzyme A cofactor affinities, and the M-acetyltransferase catalytic activities of the wild-type and 14 different mutant or chimeric human NAT2 alleles expressed in an Escherichla coll JM105 expression system. NAT2 alleles contained nucleic acid substitutions at positions 191(G->A; Arg84->Gln), 282(C—T; silent), 341(T->C; He114->Thr), 481(C->T; silent), 590(G->A; Arg197->GIn), 803(A->G; Lys268-Arg), 857(G->A; Gly288->Glu) and various combinations (282/590; 282/803; 282/857; 341/481; 341/803; 441/481/803; 481/803) of the 870 base pair NAT2 coding region. Expression of all 15 NAT2 alleles produced immunoreactlve NAT2 protein with W-acetylatlon activity. NAT2 proteins encoded by alleles with nucleic acid substitutions at positions 191, 341, 590, 282/590, 341/481, 341/803, and 341/481/803 exhibited arylamlne W-acetyltransferase maximum velocities significantly (P<0.001) lower than the wild-type NAT2. Thus, nucleic acid substitutions at positions 191, 341, and 590 either alone or in combination with other silent or conservative amino acid substitutions were sufficient to result in NAT2 proteins with significant reductions in W-acetylation activities. The recombinant NAT2 proteins also showed relative differences in intrinsic stability following incubation at 37°C and 50°C. NAT2 encoded by alleles with nucleotide substitutions at positions 191 and 857 were particularly unstable relative to the wild type. These findings using recombinant NAT2 allozymes provide important insight into the molecular genetic basis for human slow acetylator phenotype.


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