Expression of monomorphic arylamine N-acetyltransferase (NAT1) in human leukocytes.
The expression of arylamine N-acetyltransferase (NAT) in leukocytes was investigated using p-aminobenzoic acid (PABA) and sulfamethazine (SMZ), substrates which are preferentially acetylated by the monomorphic NAT1 and polymorphic NAT2 enzymes, respectively. Activity towards both substrates was detected in mononuclear leukocytes (MNL; preparation containing approximately 80% lymphocytes), monocytes and neutrophils. PABA and SMZ acetylation rates were highly correlated in each of the isolated cell types. The NAT in leukocytes displayed a much higher affinity and turnover rate for the acetylation of PABA than for SMZ. These kinetic characteristics suggest that the acetylating activity in human leukocytes is predominantly attributable to the monomorphic enzyme NAT1. Neutrophils showed evidence of biphasic kinetics for SMZ which would indicate the coexpression of NAT1 and low levels of the polymorphic enzyme, NAT2. NAT activity in MNL was not influenced by the acetylator phenotype of the individual. There was, however, a significant correlation between NAT activity in MNL and the in vivo acetylation (urinary metabolite ratio) of p-aminosalicylic acid, which is monomorphically acetylated in humans. The expression of NAT1 in leukocytes and the virtuall absence of NAT2 may have important toxicological implications. The in vitro/in vivo correlation suggests that leukocytes may be a useful marker of systemic NAT1 activity.
Cribb
A E
AE
Department of Pharmacology, University of Toronto, Ontario, Canada.
Grant
D M
DM
Miller
M A
MA
Spielberg
S P
SP
D010129:4-Aminobenzoic Acid / Q000097:blood; D000105:Acetyl Coenzyme A / Q000097:blood; D000107:Acetylation; D000328:Adult; D000368:Aged; D001191:Arylamine N-Acetyltransferase / Q000097:blood*; D002110:Caffeine / Q000652:urine; D005260:Female; D006801:Humans; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000201:enzymology*; D008099:Liver / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000201:enzymology; D009504:Neutrophils / Q000201:enzymology; D010641:Phenotype; D013418:Sulfamethazine / Q000097:blood
D002110:Caffeine; D013418:Sulfamethazine; D000105:Acetyl Coenzyme A; D001191:Arylamine N-Acetyltransferase; D010129:4-Aminobenzoic Acid