Activation of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b] pyridine by cDNA-expressed human and rat arylsulfotransferases.
Sulfation plays an obligatory role in the activation of N-hydroxy derivatives of carcinogenic arylamine (amide)s and heterocyclic amines. We found that the hepatic sulfotransferase-mediated covalent binding of 3H-labeled 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b] pyridine (N-OH-PhIP) to calf thymus DNA was 3.3 and 12.9 times higher with human cytosol preparation than with male and female rat cytosol preparations, respectively, in the presence of 3'-phosphoadenosine 5'-phosphosulfate. To assess the activating capacities of individual phenol-sulfating sulfotransferases, five different forms, human ST1A2 and ST1A3 and rat ST1A1, ST1B1 and ST1C1, were expressed in heterologous cells. All five sulfotransferases mediated the activation of N-OH-PhIP to DNA-bound products. The extents of the binding, however, differed considerably among these forms. Human ST1A2 and ST1A3 mediated the activation of N-OH-PhIP at 5.2- and 6.2-fold higher rates than did rat ST1C1, a main N-hydroxy-2-acetylaminofluorene-activating sulfotransferase, in rat liver. Extents of the binding of N-OH-PhIP in human hepatic cytosols of different individuals were positively correlated with the contents of immunoreactive ST1A2/3. These results suggest a potential role of human liver sulfotransferases in N-OH-PhIP activation. In contrast, the low sulfotransferase-mediated activation of N-OH-PhIP in rat liver is consistent with the lack of PhIP hepatocarcinogenicity in this species.
Department of Pharmacology, School of Medicine, Keio University, Tokyo.
S
S
Ozawa
H C
HC
Chou
F F
FF
Kadlubar
K
K
Nagata
Y
Y
Yamazoe
R
R
Kato
D000595:Amino Acid Sequence; D000818:Animals; D015239:Arylsulfotransferase / Q000737:chemistry / Q000378:metabolism*; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism* / Q000633:toxicity; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003600:Cytosol / Q000201:enzymology; D004247:DNA / Q000378:metabolism; D004926:Escherichia coli; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000378:metabolism* / Q000633:toxicity; D008099:Liver / Q000201:enzymology*; D008297:Male; D008969:Molecular Sequence Data; D010724:Phosphoadenosine Phosphosulfate / Q000378:metabolism; D051381:Rats; D013045:Species Specificity
D002273:Carcinogens; D007093:Imidazoles; D010724:Phosphoadenosine Phosphosulfate; D004247:DNA; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D015239:Arylsulfotransferase