Bioactivation of 3-aminobenzanthrone, a human metabolite of the environmental pollutant 3-nitrobenzanthrone: evidence for DNA adduct formation mediated by cytochrome P450 enzymes and peroxidases

被引:48
作者
Arlt, VM
Henderson, CJ
Wolf, CR
Schmeiser, HH
Phillips, DH
Stiborova, M
机构
[1] Inst Canc Res, Sect Mol Carcinogenesis, Sutton SM2 5NG, Surrey, England
[2] Ctr Biomed Res, Canc Res UK, Mol Pharmacol Unit, Dundee DD1 9SY, Scotland
[3] German Canc Res Ctr, Div Mol Toxicol, D-69120 Heidelberg, Germany
[4] Charles Univ Prague, Fac Sci, Dept Biochem, Prague 12840 2, Czech Republic
关键词
3-aminobenzanthrone; 3-nitrobenzanthrone; myeloperoxidase; cytochrome P450; DNA adducts; P-32-postlabelling;
D O I
10.1016/j.canlet.2005.03.035
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
3-Nitrobenzanthrone (3-NBA) is a suspected human carcinogen found in diesel exhaust and ambient air pollution. The main metabolite of 3-NBA, 3-aminobenzanthrone (3-ABA), was detected in the urine of salt mining workers occupationally exposed to diesel emissions. We evaluated the role of hepatic cytochrome P450 (CYP) enzymes in the activation of 3-ABA in vivo by treating hepatic cytochrome P450 oxidoreductase (POR)-null mice and wild-type littermates intraperitoneally with 0.2 and 2 mg/kg body weight of 3-ABA. Hepatic POR-null mice lack POR-mediated CYP enzyme activity in the liver. Using the P-32-postlabelling method, multiple 3-ABA-derived DNA adducts were observed in liver DNA from wild-type mice, qualitatively similar to those formed in incubations using human hepatic microsomes. The adduct pattern was also similar to those formed by the nitroaromatic counterpart 3-NBA and which derive from reductive metabolites of 3-NBA bound to purine bases in DNA. DNA binding by 3-ABA in the livers of the null mice was undetectable at the lower dose and substantially reduced (by up to 80%), relative to wild-type mice, at the higher dose. These data indicate that POR-mediated CYP enzyme activities are important for the oxidative activation of 3-ABA in livers, confirming recent results indicating that CYP-1A1 and -1A2 are mainly responsible for the metabolic activation of 3-ABA in human hepatic microsomes. No difference in DNA binding was found in kidney and bladder between null and wild-type mice, suggesting that cells in these extrahepatic organs have the metabolic capacity to oxidize 3-ABA to species forming the same 3-ABA-derived DNA adducts, independently from the CYP-mediated oxidation in the liver. We determined that different model peroxidases are able to catalyse DNA adduct formation by 3-ABA in vitro. Horseradish peroxidase (HRP), lactoperoxidase (LPO), myeloperoxidase (MPO), and prostaglandin H synthase (PHS) were all effective in activating 3-ABA in vitro, forming DNA adducts qualitatively similar to those formed in vivo in mice treated with 3-ABA and to those found in DNA reacted with N-hydroxy-3-aminobenzanthrone (N-OH-ABA). Collectively, these results suggest that both CYPs and peroxidases may play an important role in metabolizing 3-ABA to reactive DNA adduct forming species. (c) 2005 Elsevier Ireland Ltd. All rights reserved.
引用
收藏
页码:220 / 231
页数:12
相关论文
共 42 条
[31]   Mechanism of peroxidase-mediated oxidation of carcinogenic o-anisidine and its binding to DNA [J].
Stiborová, M ;
Miksanová, M ;
Havlícek, V ;
Schmeiser, HH ;
Frei, E .
MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS, 2002, 500 (1-2) :49-66
[32]   Evidence for reductive activation of carcinogenic aristolochic acids by prostaglandin H synthase -: 32P-postlabeling analysis of DNA adduct formation [J].
Stiborová, M ;
Frei, E ;
Breuer, A ;
Wiessler, M ;
Schmeiser, HH .
MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS, 2001, 493 (1-2) :149-160
[33]   Human enzymes involved in the metabolic activation of carcinogenic aristolochic acids:: Evidence for reductive activation by cytochromes P450 1A1 and 1A2 [J].
Stiborová, M ;
Frei, E ;
Wiessler, M ;
Schmeiser, HH .
CHEMICAL RESEARCH IN TOXICOLOGY, 2001, 14 (08) :1128-1137
[34]  
Stiborova Marie, 1991, Drug Metabolism and Drug Interactions, V9, P177
[35]   ABA-C15:: A new dye for probing solvent relaxation in phospholipid bilayers [J].
Sykora, J ;
Mudogo, V ;
Hutterer, R ;
Nepras, M ;
Vanerka, J ;
Kapusta, P ;
Fidler, V ;
Hof, M .
LANGMUIR, 2002, 18 (24) :9276-9282
[36]   THE PRESENCE OF MUTAGENS CARCINOGENS IN THE EXCISED LUNG AND ANALYSIS OF LUNG-CANCER INDUCTION [J].
TOKIWA, H ;
SERA, N ;
HORIKAWA, K ;
NAKANISHI, Y ;
SHIGEMATU, N .
CARCINOGENESIS, 1993, 14 (09) :1933-1938
[37]   Outdoor air pollution and lung cancer: Recent epidemiologic evidence [J].
Vineis, P ;
Forastiere, F ;
Hoek, G ;
Lipsett, M .
INTERNATIONAL JOURNAL OF CANCER, 2004, 111 (05) :647-652
[38]   Carcinogen substrate specificity of human COX-1 and COX-2 [J].
Wiese, FW ;
Thompson, PA ;
Kadlubar, FF .
CARCINOGENESIS, 2001, 22 (01) :5-10
[39]  
Williams JA, 2000, CANCER RES, V60, P4667
[40]   Determination of the enzymes responsible for activation of the heterocyclic amine 2-amino-3-methylimidazo [4,5-f]quinoline in the human breast [J].
Williams, JA ;
Stone, EM ;
Millar, BC ;
Gusterson, BA ;
Grover, PL ;
Phillips, DH .
PHARMACOGENETICS, 1998, 8 (06) :519-528