Fluoranthene metabolism: human and rat liver microsomes display different stereoselective formation of the trans-2,3-dihydrodiol

Abstract

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.

Effect of dietary fat on metabolism and DNA adduct formation after acute oral exposure of F-344 rats to fluoranthene☆

“…Biotransformation studies of FLA using microsomal preparations from rodent liver tissues revealed that 1-, 3-and 8-hydroxyfluoranthenes, 2,3-dihydro-2,3-dihydroxy FLA and FLA 2,3-dione were the predominant metabolites [28,[41][42][43]. FLA 2,3-diol, one of the predominant metabolites found in our study, has been reported to constitute 29-43% and 70-95% of the total metabolite concentrations in the rat [28] and human [44] hepatic microsomes, respectively. Hydroxyfluoranthenes are not mutagenic in their normal form but may be oxidized to their potentially mutagenic diol counterparts.…”

Cancer Risk Assessment, Indicators, and Guidelines for Polycyclic Aromatic Hydrocarbons in the Ambient Air

“…It has been shown, however, that fluoranthene is metabolized to the corresponding DEs by human liver microsomes (Day et al 1992).…”

Effects of Bulky Polycyclic Aromatic Hydrocarbon Adducts on DNA Replication by Exonuclease-Deficient T7 and T4 DNA Polymerases

“…The FADE was synthesized from > 99.9% pure ira«j-2,3-dihydroxy-2,3-dihydrofluoranthene (Day et al, 1992) by epoxidation with 3-chloroperbenzoic acid in CHCI3 and purified by medium-pressure chromatography (dry N2) over DEAE cellulose (Rastetter et al, 1982;Day et al, 1992) MS (miz, % base): 253 (100, [M+H]+). The CPPE was synthesized from 2 mg of CPP (NCI Chemical Carcinogen Repository) that was previously purified to >99% by several flash Si02 Chromatographie runs (petroleum ether).…”