Metabolism of dibenz[a,h]acridine by rat liver microsomes

As part of a project to assess the effect of heterocyclic nitrogenin modifying the metabolism and mutagenicity of polycyclic aromatichydrocabons, we investigated the metabolism of dibenz[a,h]acridine(DB[a,h]AC) by liver microsomes prepared from male Sprague-Dawleyrats. During a 6-min incubation 21, 14, 0.7 or 0.2 nmol DB[a,h]ACper mg protein were metabolized by microsomes from rats pre-treatedwith DB[a,h]AC, 3-methylcholanthrene (3-MC), phenobarbital (PB)or corn oil, respectively. In each case the predominant metaboliteswere the dihydrodiols with bay-region double bonds, namely,DB[a,h]AC-3,4-dihydrodiol and DB[a,h]AC-10,11-dihydrodiol, eachof which accounted for 21–23% of the total metabolismdetermined during a 7-min incubation with microsomes from 3-MC-treatedrats. Other metabolites produced by these microsomes includedDB[a,h]AC-l,2-dihydrodiol ({small tilde}5% of total metabolites);two K-region oxides [DB[a,h]AC-12,13- and 5,6-oxides (estimatedto represent 5% and 2% of total metabolites, respectively)];several unidentified polar metabolites (10–15%) and severalunidentified metabolites which co-eluted with 3-hydroxy-DB[a,h]AC(20%). DB[a,h]AC-8,9-dihydrodiol was not detected (<2%).The metabolite profiles produced by microsomes prepared fromrats pretreated with DB[a,h]AC, PB or corn oil were very similarto the profile produced by 3-MC-induced microsomes. We concludethat: (i) the potentially mutagenic benzo-ring dihydrodiolswith bay-region double bonds are the predominant metaboliteof DB[a,h]AC; (ii) the heterocyclic nitrogen atom has littleeffect in modifying the relative extents of formation of thesetwo benzo-ring dihydrodiols with bay-region double bonds; (iii)metabolism at the K-region is only a minor pathway for DB[a,h]AC,as is also true for the carbon analogue dibenz[a,h]anthracene;and (iv) induction by a 3-MC-type inducer (e.g. DB[a,h]AC) isrequired for substantial metabolism to occur.