Journal Article

Metabolic activation of the environmental contaminant 3-nitrobenzanthrone by human acetyltransferases and sulfotransferase

Volker M. Arlt, Hansruedi Glatt, Eva Muckel, Ulrike Pabel, Bernd L. Sorg, Heinz H. Schmeiser and David H. Phillips

in Carcinogenesis

Volume 23, issue 11, pages 1937-1945
Published in print November 2002 | ISSN: 0143-3334
Published online November 2002 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/23.11.1937
Metabolic activation of the environmental contaminant 3-nitrobenzanthrone by human acetyltransferases and sulfotransferase

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3-Nitrobenzanthrone (3-NBA) an extremely potent mutagen and suspected human carcinogen identified in diesel exhaust and in airborne particulate matter was shown to form multiple DNA adducts in vitro and in vivo in rats. In order to investigate whether human N,O-acetyltransferases (NATs) and sulfotransferases (SULTs) contribute to the metabolic activation of 3-NBA we used a panel of newly constructed Chinese hamster lung fibroblast V79MZ derived cell lines expressing human NAT1, human NAT2 or human SULT1A1, as well as TA1538-derived Salmonella typhimurium strains expressing human NAT1 (DJ400) or human NAT2 (DJ460) and determined DNA binding and mutagenicity. The formation of 3-NBA-derived DNA adducts was analysed by 32P-postlabelling after exposing V79 cells to 0.01 μM 3-NBA or 0.1 μM N-acetyl-N-hydroxy-3-aminobenzanthrone (N-Ac-N-OH-ABA), a potential metabolite of 3-NBA. Similarly up to four major and two minor adducts were detectable for both compounds, the major ones being identical to those detected previously in DNA from rats treated with 3-NBA. Comparison of DNA binding between different V79MZ derived cells revealed that human NAT2 and, to a lesser extent, human NAT1 and human SULT1A1, contribute to the genotoxic potential of 3-NBA and N-Ac-N-OH-ABA to form DNA adducts. However, the extent of DNA binding by 3-NBA was higher in almost all V79 cells at a 10-fold lower concentration than by N-Ac-N-OH-ABA, suggesting that N-Ac-N-OH-ABA is not a major intermediate in the formation of 3-NBA-derived adducts. 3-NBA showed a 3.8-fold and 16.8-fold higher mutagenic activity in Salmonella strains expressing human NAT1 and human NAT2, respectively, than in the acetyltransferase-deficient strain, whereas N-Ac-N-OH-ABA was only clearly (but weakly) mutagenic in Salmonella DJ460 expressing human NAT2. This finding suggests that N-Ac-N-OH-ABA is not a major reactive metabolite responsible for the high mutagenic potency of 3-NBA in Salmonella. Collectively our results indicate that O-acetylation and O-sulfonation by human NATs and SULTs may contribute significantly to the high mutagenic and genotoxic potential of 3-NBA. Moreover, the yet-unidentified four major 3-NBA-derived adducts may be DNA adducts without an N-acetyl group.

Keywords: 3-ABA, 3-aminobenzanthrone; CYP, cytochrome P450; dA, 2′-deoxyadenosine; dA-N-Ac-ABA, structurally unidentified 2′-deoxyadenosine adduct; dG, 2′-deoxyguanosine; dG-N-Ac-ABA, N-acetyl-3-amino-2-(2′-deoxyguanosin-8-yl)benzanthrone; dGp-N-Ac-ABA, N-acetyl-3-amino-2-(2′-deoxyguanosin-3′-monophosphate-8-yl)benzanthrone; NAT, N,O-acetyltransferase; N-Ac-N-OH-ABA, N-acetyl-N-hydroxy-3-aminobenzanthrone; N-Aco-N-Ac-ABA, N-acetoxy-N-acetyl-3-aminobenzanthrone; 3-NBA, 3-nitrobenzanthrone; N-OH-ABA, N-hydroxy-3-aminobenzanthrone; PAH, polycyclic aromatic hydrocarbon; RAL, relative adduct labelling; SULT, sulfotransferase; TLC, thin-layer chromatography.

Journal Article.  6742 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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