Activation and metabolism of benz[j]aceanthrylene-9,10-dihydrodiol, the precursor to bay-region metabolism of the genotoxic cyclopenta-PAH benz[j]aceanthrylene

Add time:09/02/2019    Source:sciencedirect.com

Benz[j]aceanthrylene, a cyclopentafused polycyclic aromatic hydrocarbon produced in combustion emissions, possesses a bay region and an etheno bridge which may both contribute to the overall genotoxicity of the compound. In order to assess the role of activation at the bay region, the precursor epoxide benz[j]aceanthrylene 9,10-oxide, its dehydration product 10-hydroxybenz[j]aceanthrylene, the key dihydrodiol 9,10-dihydroxy-9,10-dihydrobenz[j]aceanthrylene and the bay-region diol-epoxide 7,8- epoxy-9,10-dihydroxy-7,8,9,10-tetrahydrobenz[j]aceanthrylene were evaluated in the bacterial histidine-reversion plate incorporation assay (Ames assay) with Salmonella typhimurium strain TA98. The diol-epoxide alone showed direct-acting mutagenicity (10 revertants per nmole), which was decreased by addition of exogenous metabolic activation (Aroclor 1254-treated rat-liver S9), whereas all the other compounds tested were activated by increasing concentrations of S9. The potency of the diol-epoxide was not sufficient to account for the activity of the parent compound. Identification by proton nuclear magnetic resonance and mass spectrometry of the major products of further metabolism by Aroclor 1254-treated rat-liver S9 of the bay region precursor dihydrodiol 9,10-dihydroxy-9,10- dihydrobenz[j]aceanthrylene indicated that oxidation occurred predominantly at the etheno bridge, to give 9,10-dihydroxy-9,10-dihydrobenz[j]aceanthrylene-2(1H)-one, arising by (non-enzymic) rearrangement of the etheno bridge epoxide and the tetrol 1,2,9,10-tetrahydroxy-1,2,9,10-tetrahydrobenz[j]acenthrylene. The bay region tetrol 7,8,9,10-tetrahydroxy-7,8,9,10-tetrahydrobenz[j]aceanthrylene was observed, implying further bay-region metabolism; re-aromatization of the benzo ring to benz[j]aceanthrylene-9,10-diol also occurred. Thus oxidation at the etheno bridge accounts for the majority of the activity of benz[j]aceanthrylene and its derivatives when Aroclor 1254-treated rat-liver S9 is used for exogenous metabolic activation.

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