Acetylator genotype-dependent metabolic activation of carcinogenic N-hydroxyarylamines by S-acetyl coenzyme A-dependent enzymes of inbred hamster tissue cytosols: relationship to arylamine N-acetyltransferase.
A genetic polymorphism in S-acetyl coenzyme A (AcCoA)-dependent N-acetyltransferase has been associated with a differential risk for certain cancers in humans. In this study, several tissues from the inbred Syrian hamster with a genetically defined AcCoA-dependent N-acetyltransferase polymorphism (homozygous rapid acetylator, Bio. 87.20; homozygous slow acetylator, Bio. 82.73/H; and heterozygous acetylator, Bio. 87.20 X Bio. 82.73/H F1), were investigated for the relationship of arylamine N-acetyltransferase to the AcCoA-dependent metabolic activation of carcinogenic N-hydroxy (N-OH)-arylamines to bind to DNA (O-acetyltransferase). The levels of both 2-aminofluorene (AF) N-acetyltransferase and N-OH-AF O-acetyltransferase activity reflected the N-acetylator genotype in liver, intestine, kidney and lung cytosols. A significant acetylator gene--dose response for AF N-acetyltransferase and N-OH-AF O-acetyltransferase activities was observed in liver and lung cytosols. In contrast, acetylator genotype was not consistently expressed for the AcCoA-dependent N-acetylation of 4-aminobiphenyl (ABP), nor for the AcCoA-dependent metabolic activation of N-OH-ABP and N-OH-3,2'-dimethyl-4-aminobiphenyl in these same tissue cytosols. Two peaks of acetyltransferase activity were partially purified by ion exchange FPLC chromatography from the hepatic cytosol of both the homozygous rapid and homozygous slow acetylator hamster. In contrast to unfractionated cytosol, the isozyme(s) eluting first clearly demonstrated levels of AcCoA-dependent arylamine N-acetyltransferase and N-OH-arylamine O-acetyltransferase activities that were consistent with N-acetylator genotype (polymorphic) for all substrates tested. In contrast, the slower eluting isozyme(s) in each acetylator cytosol showed levels of AcCoA-dependent N- and O-acetyltransferase activities that did not vary with N-acetylator genotype (monomorphic). The AcCoA-dependent O-acetyltransferase activity of both the monomorphic and polymorphic peaks was paraoxon resistant. These studies demonstrate acetylator genotype-dependent control of AcCoA-dependent metabolic activation of N-OH-arylamines(O-acetylation) by polymorphic isozyme(s) similar to that for AcCoA-dependent N-acetylation of arylamines in the hamster. The polymorphic genetic control of N-OH-arylamine O-acetyltransferase may be an important risk factor for arylamine-induced cancer, in those species and tissues expressing appreciable levels of O-acetyltransferase activity.
Hein
D W
DW
Department of Pharmacology, Morehouse School of Medicine, Atlanta, GA 30310-1495.
Flammang
T J
TJ
Kirlin
W G
WG
Trinidad
A
A
Ogolla
F
F
D000105:Acetyl Coenzyme A / Q000378:metabolism*; D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism*; D000611:Aminobiphenyl Compounds / Q000493:pharmacokinetics; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism*; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D003600:Cytosol / Q000201:enzymology*; D005449:Fluorenes / Q000493:pharmacokinetics; D006720:Homozygote; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000201:enzymology; D008168:Lung / Q000201:enzymology; D008647:Mesocricetus; D010261:Paraoxon / Q000494:pharmacology; D011110:Polymorphism, Genetic
D000611:Aminobiphenyl Compounds; D002273:Carcinogens; D005449:Fluorenes; D007527:Isoenzymes; C001368:N-hydroxy-2-aminofluorene; C014593:N-hydroxy-4-aminobiphenyl; D000105:Acetyl Coenzyme A; C044345:N-hydroxy-3,2'-dimethyl-4-aminobiphenyl; D000123:Acetyltransferases; D001191:Arylamine N-Acetyltransferase; D010261:Paraoxon