Activation of 2‐Hydroxyamino‐l‐methyl‐6‐phenylimidazo[4,5‐b]pyridne 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.