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Abstract
2-Nitrobenzo[a]pyrene (2-nitro-BaP) induced 100% liver tumor incidence in the neonatal mouse tumorigenicity assay and exhibited the highest mutagenicity among the 1-, 2-, 3-, and 6-nitro-BaP when tested in Salmonella typhimurium TA98 and TA100. To determine the metabolic activation pathways leading to tumor initiation and mutation induction, we have studied the aerobic metabolism of 2-nitro-BaP by Sprague-Dawley rat and B6C3F1 mouse liver microsomes. Metabolites were isolated by HPLC and characterized by spectral analyses, including UV-visible absorption, mass and proton NMR spectroscopy. With both rat and mouse liver microsomes, 2-nitro-BaP trans-9,10-dihydrodiol and 2-nitro-BaP trans-7,8-dihydrodiol were formed as the predominant metabolites, and 2-nitro-BaP 7,8,9,10-tetrahydrotetrol was produced in trace quantities. 2-Nitro-BaP and its two dihydrodiol metabolites were assayed in Salmonella typhimurium tester strain TA98. 2-Nitro-BaP trans-7,8-dihydrodiol, in the presence of S9, was the most mutagenic (6156±288 revertants/plate). The overall results suggest that ring-oxidation of 2-nitro-BaP to the bay-region diol-epoxide, 2-nitro-BaP trans-7,8-diol-anti-9,10-epoxide, is a principal metabolic activation pathway.
