Polymorphic expression of acetyl coenzyme A-dependent arylamine N-acetyltransferase and acetyl coenzyme A-dependent O-acetyltransferase-mediated activation of N-hydroxyarylamines by human bladder cytosol.
Human epidemiological studies suggest a genetic predisposition to bladder cancer among slow N-acetylators. The capacity of human bladder to N-acetylate arylamines, catalyzed by acetyl coenzyme A-dependent N-acetyltransferase(s) (EC 2.3.1.5) (NAT), may be an important step in the activation and/or deactivation of arylamines in the pathways leading to the initiation of bladder cancer. Another possible activation step is the direct O-acetylation of N-hydroxyarylamines via O-acetyltransferase(s) (OAT) to DNA-binding electrophiles. Human bladder cytosol from nine fresh autopsy specimens were investigated for NAT activity towards p-aminobenzoic acid, and the arylamine carcinogens 4-aminobiphenyl, 2-aminofluorene, and beta-naphthylamine. Apparent Km determinations indicated little difference in NAT affinity (100-300 microM) for any of the substrates between the nine individual bladders. However, the apparent Vmax determinations indicated that the bladders could be classified into rapid or slow acetylator phenotypes based on their NAT activity towards 4-aminobiphenyl, 2-aminofluorene, and beta-naphthylamine. Four of the bladder cytosols had mean activities significantly (P less than 0.01) higher (approximately 10-fold) than the mean NAT activities of the other five bladder cytosols towards each arylamine carcinogen. However, no significant difference was detected in their NAT activities using p-aminobenzoic acid as a substrate. The human bladder cytosols were also tested for their capacity to activate N-hydroxy-3,2'-dimethyl-4-aminobiphenyl to a DNA-binding electrophile through a direct OAT-mediated catalysis. The N-hydroxyarylamine OAT activity also discriminated between two levels of activation, being significantly (P = 0.0002) higher (about twofold) in the rapid N-acetylator bladder cytosols, that correlated (r = 0.94) with the measured levels of NAT activity in each bladder cytosol. These results suggest that NAT activity and OAT activity of the human bladder vary concordantly with N-acetylator phenotype. The polymorphic expression of these acetylation activities may be important risk factors in human susceptibility to bladder cancer from arylamine carcinogens.
Kirlin
W G
WG
Department of Pharmacology, Morehouse School of Medicine, Atlanta, Georgia 30310.
Trinidad
A
A
Yerokun
T
T
Ogolla
F
F
Ferguson
R J
RJ
Andrews
A F
AF
Brady
P K
PK
Hein
D W
DW
D015081:2-Naphthylamine / Q000378:metabolism; D010129:4-Aminobenzoic Acid / Q000378:metabolism; D000105:Acetyl Coenzyme A / Q000378:metabolism*; D000123:Acetyltransferases / Q000032:analysis*; D000611:Aminobiphenyl Compounds / Q000378:metabolism; D001191:Arylamine N-Acetyltransferase / Q000032:analysis*; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D005449:Fluorenes / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D011110:Polymorphism, Genetic; D001743:Urinary Bladder / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced
D000611:Aminobiphenyl Compounds; D002273:Carcinogens; D005449:Fluorenes; C006757:4-biphenylamine; C012177:2-aminofluorene; D000105:Acetyl Coenzyme A; D004247:DNA; D015081:2-Naphthylamine; D000123:Acetyltransferases; D001191:Arylamine N-Acetyltransferase; D010129:4-Aminobenzoic Acid