Fluoranthene metabolism: human and rat liver microsomes display different stereoselective formation of the trans-2,3-dihydrodiol.
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.
Day
B W
BW
Department of Environmental & Occupational Health, University of Pittsburgh, Pennsylvania 15238.
Sahali
Y
Y
Hutchins
D A
DA
Wildschütte
M
M
Pastorelli
R
R
Nguyen
T T
TT
Naylor
S
S
Skipper
P L
PL
Wishnok
J S
JS
Tannenbaum
S R
SR
D000818:Animals; D001140:Aroclors / Q000494:pharmacology; D001711:Biotransformation; D002274:Carcinogens, Environmental / Q000378:metabolism* / Q000633:toxicity; D020111:Chlorodiphenyl (54% Chlorine); D002851:Chromatography, High Pressure Liquid; D004852:Epoxy Compounds / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D005449:Fluorenes / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D006207:Half-Life; D006801:Humans; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism*; D008968:Molecular Conformation; D009152:Mutagenicity Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D012486:Salmonella typhimurium / Q000235:genetics; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism
D001140:Aroclors; D002274:Carcinogens, Environmental; D004852:Epoxy Compounds; D005449:Fluorenes; D020111:Chlorodiphenyl (54% Chlorine); C007738:fluoranthene