Carcinogenesis, Vol. 21, No. 7, 1347-1354,
July 2000
© 2000 Oxford University Press
Carcinogenesis |
In vitro bioactivation of N-hydroxy-2-amino-
-carboline
Division of Molecular Epidemiology, National Center for Toxicological Research, 3900 NCTR Road, Jefferson, AR 72079-9502, USA
2-Amino-
-carboline (AC) is a mutagenic and carcinogenic heterocyclic amine present in foods cooked at high temperature and in cigarette smoke. The mutagenic activity of AC is dependent upon metabolic activation to N-hydroxy-AC (N-OH-AC); however, the metabolism of N-OH-AC has not been studied. We have synthesized 2-nitro--carboline and N-OH-AC and have examined in vitro bioactivation of N-OH-AC by human and rodent liver cytosolic sulfotransferase(s) and acetyltransferase(s) and by recombinant human N-acetyltransferases, NAT1 and NAT2. The sulfotransferase-dependent bioactivation of N-OH-AC by human liver cytosol exhibited large inter-individual variation (0.5–75, n = 14) and was significantly higher than bioactivation of N-hydroxy-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhIP). Correlation and inhibition studies suggested that the isoform of sulfotransferase primarily responsible for bioactivation of N-OH-AC in human liver cytosol is SULT1A1. O-Acetyltransferase-dependent bioactivation of N-OH-AC by human liver cytosol also exhibited large inter-individual variation (16–192, n = 18). In contrast to other N-hydroxy heterocyclic amines, which are primarily substrates only for NAT2, both NAT1 and NAT2 catalyzed bioactivation of N-OH-AC. The rate of bioactivation of N-OH-AC by both NAT1 and NAT2 was significantly higher than that for N-OH-PhIP. In rat and mouse liver cytosols, the level of sulfotransferase-dependent bioactivation of N-OH-AC was similar to the level in the high sulfotransferase activity human liver cytosol. The level of O-acetyltransferase-dependent bioactivation of N-OH-AC in rat liver cytosol was also comparable with that in the high acetyltransferase activity human liver cytosol. However, the level of O-acetyltransferase-dependent bioactivation of N-OH-AC in mouse liver cytosol was comparable with that in the low acetyltransferase activity human liver cytosol. In contrast to N-OH-PhIP, bioactivation of N-OH-AC was not inhibited by glutathione S-transferase activity; however, DNA binding of N-acetoxy-AC was inhibited 20% in the presence of GSH. These results suggest that bioactivation of N-OH-AC may be a significant source of DNA damage in human tissues after dietary exposure to AC and that the relative contribution of each pathway to bioactivation or detoxification of N-OH-AC differs significantly from other N-hydroxy heterocyclic or aromatic amines.
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