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Oxidation of cyclopenta[cd]pyrene (CPP) by mouse and human liver microsomes was used to produce several previously undescribed metabolites, which were separated and isolated by reversed-phase HPLC. Three of these, 3,4-dihydroCPP-c-3,4-diol, 4-hydroxy-3,4-dihydroCPP, and 4-oxo-3,4-dihydroCPP, were fully characterized by GC-MS and UV spectroscopic analysis as well as by total synthesis. Two additional pairs of metabolites were identified as isomeric tetrahydrotetrols and dihydrotriols by GC-MS analysis of their trimethylsilyl derivatives. Their UV spectra were recorded and found to agree with the structure assignments. The tetrahydrotetrols were further characterized by the fact that either 3,4- or 9,10-trans-dihydrodiol could serve as their precursor, indicating that they are the two diastomeric 3,4,9,10-tetrahydroCPP-t-3,4-t-9,10-tetrols. The dihydrotriols were shown to possess t-3,4-dihydrodiol functionality. As found previously using rat liver microsomes, the most abundant metabolite was 3,4-dihydroCPP-t-3,4-diol. It was produced with one enantiomer in severalfold excess over the other, and the major enantiomer was shown to have 3R,4R configuration by exciton chirality circular dichroism. Microsomal oxidation of [4-2H]CPP, which was synthesized for this study, was used to determine the mechanisms of formation of 4-oxo- and 4-hydroxy-3,4-dihydroCPP. The ketone was produced without detectable retention of deuterium label, eliminating the NIH shift as a possible mechanism. The alcohol was shown to arise by NADPH-dependent reduction of both the ketone and another intermediate presumed to be the 3,4-epoxide.(ABSTRACT TRUNCATED AT 250 WORDS)

The metabolism of the environmental carcinogen fluoroanthene by human liver microsomes was compared to that by liver microsomes from rats treated with Aroclor 1254. Although the human-derived system gave primarily one product, similar metabolites were noted from each system. Enantiomers of the major metabolic product, in both cases the trans-2,3-dihydrodiol, were separated by chiral stationary-phase chromatography. Absolute configurations were assigned by application of the benzoate exciton chirality rules to the CD spectra of the 4-(dimethylamino)benzoyl esters. Liver microsomes from Aroclor 1254-treated rats produced the R,R enantiomer of the diol in 75-78% enantiomeric excess, while human liver microsomes produced this enantiomer in only 6-12% excess. The activities of these enantiomers were compared in Salmonella typhimurium strain TM677 mutagenicity assays employing the 9000g supernatant of Aroclor 1254-induced rat liver homogenates. Both the syn- and anti-2,3-dihydrodiol 1,10b-epoxides, which had only been inferred to be metabolites in previous studies, were isolated from the microsomal incubations by preparative reverse-phase HPLC. The evident exceptional aqueous stabilities of these diol epoxides were further examined by half-life determination experiments. Their tetrahydrotetrol hydrolysis products were also noted in the metabolite HPLC profiles. The structures of the tetrahydrotetrols were confirmed by total synthesis.

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