Correlation between genotype and phenotype of the human arylamine N-acetyltransferase type 1 (NAT1).

Arylamine N-acetyltransferase 1 (NAT1) conjugates several aromatic amines and their N-hydroxylated metabolites by N- or O-acetylation. NAT1 genotype and phenotype is known to be variable in human populations. In this study, we set out to measure the functional relevance of the frequent NAT1 gene variants for the activity in human red blood cells. Healthy German volunteers (N = 314) were genotyped for NAT1 alleles *3, *4, *10, *11, *14, and *15 using polymerase chain reactions and restriction fragment length pattern analysis, and NAT1 enzyme kinetic parameters were measured in a subset of 105 individuals using p-aminobenzoic acid as specific substrate. There was no functional difference between NAT1 alleles *4 and *10. In particular, there was no trend of increasing activity from NAT1*4/*4 to *4/*10 and *10/*10. Carriers of the NAT1 *11 and *14 alleles had a statistically significant lower enzyme activity compared with carriers of the *3, *4, or *10 alleles. Compared with the wild-type genotype NAT1*4/*4, activity of the NAT1*11/*11, NAT1*11/*10, and NAT1*11/*4 genotypes was reduced by 20.7%, 35.7%, and 31.5%, respectively. Activity of the NAT1*10/*14 and NAT1*4/*14 genotypes was reduced by 49.8% and 55.6%, respectively. The difference in NAT1 activity between the *4/*11 and *4/*14 genotypes was also significant (P < 0.01). The carrier of the NAT1*15/*15 genotype had no detectable enzyme activity. In conclusion, functional consequences of NAT1 mutations were tested in a large population. Activity in carriers of NAT1 alleles *3, *4, and *10 did not differ, alleles NAT1*11 and *14 appeared to be low activity alleles, and allele NAT1*15 had no activity.