Identification and characterization of variant alleles of human acetyltransferase NAT1 with defective function using p-aminosalicylate as an in-vivo and in-vitro probe
Although several variant alleles at the human NAT1 gene locus have been reported, their relationship to phenotypic variations in NAT1 function remains unclear. We have used in-vivo and invitro phenotyping tests, along with PCR-based cloning and heterologous expression, to investigate the extent of variation in NAT1 function and to characterize novel allelic variants at the NAT1 gene locus. The NAT 1 -selective substrate p-aminosalicylic acid (PAS) was used as a probe for NAT1 function. In-vivo PAS acetylation rates were estimated by determining the ratio of PAS to JV-acetylated PAS (AcPAS) in urine and plasma following the oral ingestion of Nemasol Sodium®. Excluding outliers, a 65-fold variation in the urinary AcPAS:PAS ratio was observed (n=144), while a 5.6-fold variation in the plasma AcPAS:PAS ratio was seen in a subset (n=19) of this sample. Urinary and plasma ratios correlated moderately (r=0.74, pm