Metabolic activation of N-hydroxy arylamines and N-hydroxy heterocyclic amines by human sulfotransferase(s).
Several N-hydroxy metabolites of carcinogenic arylamines and heterocyclic amines were examined as substrates for bioactivation by human liver sulfotransferases (STs). Among the N-hydroxy derivatives studied, N-hydroxy-2-acetylaminofluorene, N-hydroxy-2-aminofluorene, N-hydroxy-4,4'-methylene-bis(2-chloroaniline), N-hydroxy-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, and N-hydroxy-2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole were each metabolically activated by 3'-phosphoadenosine-5'-phosphosulfate-dependent human liver STs. No ST-mediated DNA binding of N-hydroxy-2-amino-3-methylimidazo[4,5-f]quinoline or N-hydroxy-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline was detected under our assay conditions. In the 12 human hepatic cytosols studied, the extent of 3'-phosphoadenosine-5'-phosphosulfate-dependent DNA binding of the N-hydroxy derivatives were all significantly correlated with levels of thermostable phenol ST (TS-PST) activity but not with thermolabile phenol ST or dehydroepiandrosterone ST activities. The propensity of these N-hydroxy arylamines and N-hydroxy heterocyclic amines to serve as selective substrates for human TS-PST was further confirmed by inhibition with 2,6-dichloro-4-nitrophenol and by thermostability studies. N-hydroxy-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and N-hydroxy-4,4'-methylene-bis(2-chloroaniline) were also used as substrates to study ST-dependent metabolic activation in other human tissue preparations. 3'-phosphoadenosine-5'-phosphosulfate-dependent DNA binding activity was detected in human liver and colon cytosols but not in pancreas, larynx, or urinary bladder epithelial cytosols. Since the TS-PST appears to be expressed polymorphically in human populations, the finding that human TS-PST is capable of metabolically activating N-hydroxy metabolites of several carcinogenic arylamines and heterocyclic amines suggests that TS-PST may have an important role in determining interindividual susceptibility to these environmental and dietary carcinogens.
Chou
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Office of Research (HFT-100) National Center for Toxicological Research, Jefferson, Arkansas 72079.
Lang
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Kadlubar
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D000588:Amines / Q000378:metabolism*; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D003106:Colon / Q000201:enzymology; D003600:Cytosol / Q000201:enzymology; D004247:DNA / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006898:Hydroxylamines / Q000378:metabolism*; D006900:Hydroxylation; D007700:Kinetics; D007830:Larynx / Q000201:enzymology; D008099:Liver / Q000201:enzymology*; D010179:Pancreas / Q000201:enzymology; D013379:Substrate Specificity; D015238:Sulfotransferases / Q000378:metabolism*
D000588:Amines; D002273:Carcinogens; D006571:Heterocyclic Compounds; D006898:Hydroxylamines; D004247:DNA; D015238:Sulfotransferases