Journal Article

<i>In vitro</i> bioactivation of <i>N</i>-hydroxy-2-amino-α-carboline

Roberta S. King, Candee H. Teitel and Fred F. Kadlubar

in Carcinogenesis

Volume 21, issue 7, pages 1347-1354
Published in print July 2000 | ISSN: 0143-3334
Published online July 2000 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/21.7.1347
In vitro bioactivation of N-hydroxy-2-amino-α-carboline

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2-Amino-α-carboline (AαC) is a mutagenic and carcinogenic heterocyclic amine present in foods cooked at high temperature and in cigarette smoke. The mutagenic activity of AαC is dependent upon metabolic activation to N-hydroxy-AαC (N-OH-AαC); however, the metabolism of N-OH-AαC has not been studied. We have synthesized 2-nitro-α-carboline and N-OH-AαC and have examined in vitro bioactivation of N-OH-AαC 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-AαC 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-AαC in human liver cytosol is SULT1A1. O-Acetyltransferase-dependent bioactivation of N-OH-AαC 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-AαC. The rate of bioactivation of N-OH-AαC 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-AαC was similar to the level in the high sulfotransferase activity human liver cytosol. The level of O-acetyltransferase-dependent bioactivation of N-OH-AαC 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-AαC 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-AαC was not inhibited by glutathione S-transferase activity; however, DNA binding of N-acetoxy-AαC was inhibited 20% in the presence of GSH. These results suggest that bioactivation of N-OH-AαC may be a significant source of DNA damage in human tissues after dietary exposure to AαC and that the relative contribution of each pathway to bioactivation or detoxification of N-OH-AαC differs significantly from other N-hydroxy heterocyclic or aromatic amines.

Keywords: AαC, 2-amino-α-carboline, 2-amino-9H-pyrido[2,3-b]indole; ABP, 4-aminobiphenyl; AcCoA; acetyl coenzyme A; AF, 2-aminofluorene; DCNP, 2,4-dichloronitrophenol; DTT, dithiothreitol; GSH, glutathione (reduced); GST, glutathione S-transferase; IQ, 2-amino-3-methylimidazo [4,5-f]quinoline; MeIQx, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline; NAT, N-acetyltransferase; N-OAc, N-acetoxy; N-OH, N-hydroxy; NO2αC, 2-nitro-α-carboline; PABA, p-aminobenzoic acid; PAPS, 3′-phosphoadenosine 5′-monophosphate; PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine; SMZ, sulfamethazine; THF, tetrahydrofuran.

Journal Article.  7190 words. 

Subjects: Clinical Cytogenetics and Molecular Genetics

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