Molecular mechanism of genotoxicity of the environmental pollutant 3-nitrobenzanthrone.
3-Nitrobenzanthrone (3-NBA) is a suspected human carcinogen identified in diesel exhaust and air pollution. This article reviews the results of our laboratories showing which of the phase I and II enzymes are responsible for 3-NBA genotoxicity, participating in activation of 3-NBA and its human metabolite, 3-aminobenzanthrone (3-ABA), to species generating DNA adducts. Among the phase I enzymes, the most of the activation of 3-NBA in vitro is attributable to cytosolic NAD(P)H:quinone oxidoreductase (NQO1), while N,O-acetyltransferase (NAT), NAT2, followed by NAT1, sulfotransferase (SULT), SULT1A1 and, to a lesser extent, SULT1A2 are the major phase II enzymes activating 3- NBA. To evaluate the importance of hepatic cytosolic enzymes in relation to microsomal NADPH:cytochrome P450 (CYP) oxidoreductase (POR) in the activation of 3-NBA in vivo, we treated hepatic POR-null and wild-type C57BL/6 mice with 3-NBA or 3-ABA. The results indicate that 3-NBA is predominantly activated by cytosolic nitroreductases such as NQO1 rather than microsomal POR. In the case of 3-ABA, CYP1A1/2 enzymes are essential for the oxidative activation of 3-ABA in liver. However, cells in the extrahepatic organs have the metabolic capacity to activate 3-ABA to form DNA adducts, independently from CYP-mediated oxidation in the liver. Peroxidases such as prostaglandin H synthase, lactoperoxidase, myeloperoxidase, abundant in several extrahepatic tissues, generate DNA adducts, which are formed in vivo by 3-ABA or 3-NBA. The results suggest that both CYPs and peroxidases may play an important role in metabolism of 3-ABA to reactive species forming DNA adducts, participating in genotoxicity of this compound and its parental counterpart, 3-NBA.
Stiborová
Marie
M
Department of Biochemistry, Charles University, Albertov 2030, 12840 Prague 2, Czech Republic. stiborov@natur.cuni.cz
Arlt
Volker M
VM
Henderson
Colin J
CJ
Wolf
C Roland
CR
Frei
Eva
E
Schmeiser
Heinz H
HH
Phillips
David H
DH
D000818:Animals; D001551:Benz(a)Anthracenes / Q000633:toxicity*; D002274:Carcinogens, Environmental / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D018736:DNA Adducts; D004785:Environmental Pollutants / Q000633:toxicity*; D004789:Enzyme Activation; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D010544:Peroxidases / Q000378:metabolism
D001551:Benz(a)Anthracenes; D002274:Carcinogens, Environmental; D018736:DNA Adducts; D004785:Environmental Pollutants; D003577:Cytochrome P-450 Enzyme System; D010544:Peroxidases; C117220:3-nitrobenzanthrone