The S-acetyl coenzyme A-dependent metabolic activation of the carcinogen N-hydroxy-2-aminofluorene by human liver cytosol and its relationship to the aromatic amine N-acetyltransferase phenotype.
A genetic polymorphism in the enzymatic N-acetylation of sulfamethazine and other drugs in humans is well known and has been related to differential susceptibility to drug toxicities. Carcinogenic aromatic amines such as 2-aminofluorene also undergo N-acetylation, and phenotypic slow acetylator individuals have been suggested to be at increased risk to arylamine-induced urinary bladder cancer. However, acetyltransferases have also been shown to catalyze a final metabolic activation step in the conversion of both hydroxamic acid (e.g. N-hydroxy-N-acetyl-2-aminofluorene N,O-acyltransferase) and N-hydroxy-arylamine (e.g. N-hydroxy-2-aminofluorene O-acetyltransferase) metabolites to DNA-bound adducts. In this regard, rapid acetylators have recently been reported to be at higher risk for colorectal cancer. In this study, we examined the enzymatic activity of 35 human liver cytosol samples (obtained surgically from organ donors) for sulfamethazine and 2-aminofluorene N-acetyltransferase activities, N-hydroxy-N-acetyl-2-aminofluorene N,O-acyltransferase activity, and the acetyl coenzyme A (CoA)-dependent O-acetylation of N-hydroxy-2-aminofluorene to form DNA-bound products. The results with sulfamethazine indicated that about two-thirds of the human liver samples were of the slow acetylator phenotype; the same individuals also exhibited levels of 2-aminofluorene N-acetylation that were consistent with their respective sulfamethazine-N-acetylation activity. N-Hydroxy-N-acetyl-2-aminofluorene N,O-acyltransferase activity was not detected. However, the acetyl CoA-dependent activation of N-hydroxy-2-aminofluorene was observed for nearly all of the samples and was consistently higher in the fast acetylator group. These data support the hypothesis that phenotypic rapid acetylator individuals are likely to be at higher risk to aromatic amine-induced cancers in those tissues containing appreciable levels of N-hydroxy arylamine O-acetyltransferase.
Flammang
T J
TJ
National Center for Toxicological Research, Jefferson, AR 72079.
Yamazoe
Y
Y
Guengerich
F P
FP
Kadlubar
F F
FF
D000105:Acetyl Coenzyme A / Q000378:metabolism*; D000123:Acetyltransferases / Q000378:metabolism*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism*; D001711:Biotransformation; D005449:Fluorenes / Q000493:pharmacokinetics*; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D010641:Phenotype; D011110:Polymorphism, Genetic
D005449:Fluorenes; D007527:Isoenzymes; C001368:N-hydroxy-2-aminofluorene; D000105:Acetyl Coenzyme A; D000123:Acetyltransferases; D001191:Arylamine N-Acetyltransferase