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AN EVALUATION OF THE MUTAGENICITY, METABOLISM AND DNA ADDUCT FORMATION OF 5-NITROBENZO[B]NAPHTHO[2,1-D]THIOPHENE
Citation:
King, L C., M. J. Kohan, J A. Ross, J. D. Allison, L D. Adams, D. Desai, S. Amin, W. Padgett, A M. Richard, AND S Nesnow. AN EVALUATION OF THE MUTAGENICITY, METABOLISM AND DNA ADDUCT FORMATION OF 5-NITROBENZO[B]NAPHTHO[2,1-D]THIOPHENE. Presented at 18th annual symposium of polycyclic aromatic compounds, University of Cincinnati, Ohio, Sept 9-13, 2001.
Description:
An Evaluation of the Mutagenicity, Metabolism and DNA Adduct Formation of 5-Nitrobenzo[b ]naphtho[2, I-d]thiophene
Thioarenes, sulfur containing polycyclic aromatic compounds, are environmental contaminants suspected of posing human health risks. In this study, 5-nitrobenzo[b ]naphtho[2, 1- d]
thiophene (5-nitro-BNT), a nitrated-thioarene, was examined for its mutagenicity, metabolism and subsequent formation ofDNA adducts. 5-Nitro-BNT was weakly mutagenic in Salmonella typhimurium strains TA98 and TA100 without Aroclor-1254-induced rat liver S9 (S9), and its activity was increased in the presence of S9. Anaerobic metabolism of 5-nitro-BNT produced one major metabolite, identified as 5-amino-BNT by NMR, MS, and UV spectroscopy and by comparison with an authentic standard. Aerobic S9 metabolism of 5-nitro-BNT produced a major metabolite, identified as trans-9, 1 0-dihydroxy-9 ,1 O-dihydro- 5-nitro- BNT ( 5-nitro- BNT - 9,10-diol). Also present were minor amounts of 5-amino-BNT and trans-9,10-dihydroxy-9,10- dihydro-5-amino-BNT (5-amino-BNT -9, 10-diol). DNA adduct analyses were performed using the 32p-postlabeling assay and reverse-phase HPLC. Three major XO-derived calf thymus DNA adducts of 5-nitro-BNT were detected: two were identified as reaction products of 5-nitro-BNT with 2'-deoxyguanosine and one with 2'-deoxy-adenosine. Treatment with allopurinol (a specific XO inhibitor) resulted in loss of all three adducts, confirming enzymatic mediation by XO. Aerobic S9 activation of 5-nitro-BNT with calf thymus DNA produced three adducts. Based on their chromatographic mobilities, two were identified as reaction products of 5-nitro-BNT with 2'-deoxyguanosine and one with 2'-deoxyadenosine. Incorporation of 1-aminobenzotriazole (a P450 inhibitor) in the incubation mixture resulted in a loss of these adducts, confirming enzymatic mediation by P450. Aerobic S9-catalyzed metabolism of 5-nitro-BNT -9, 10-diol produced the same DNA adducts as observed with 5-nitro-BNT. Aerobic S9-catalyzed metabolism of 5-amino-BNT-9,10-diol produced the same deoxyadenosine-derived DNA adducts as observed with 5-nitro-BNT and 5-nitro-BNT -9,1 O-diol. These results provide additional information that both ring oxidation and nitroreduction are involved in the metabolism, DNA adduct formation and mutagenicity of 5-nitro-BNT.
This is an abstract of a proposed presentation and does not necessarily reflect EPA policy