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

Chem Res Toxicol. 1992 Nov-Dec;5(6):779-86. doi: 10.1021/tx00030a008.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Aroclors / pharmacology
  • Biotransformation
  • Carcinogens, Environmental / metabolism*
  • Carcinogens, Environmental / toxicity
  • Chlorodiphenyl (54% Chlorine)
  • Chromatography, High Pressure Liquid
  • Epoxy Compounds / chemistry
  • Epoxy Compounds / metabolism
  • Epoxy Compounds / toxicity
  • Fluorenes / chemistry
  • Fluorenes / metabolism*
  • Fluorenes / toxicity
  • Half-Life
  • Humans
  • Mass Spectrometry
  • Microsomes, Liver / metabolism*
  • Molecular Conformation
  • Mutagenicity Tests
  • Rats
  • Rats, Sprague-Dawley
  • Salmonella typhimurium / genetics
  • Spectrophotometry, Ultraviolet
  • Stereoisomerism

Substances

  • Aroclors
  • Carcinogens, Environmental
  • Epoxy Compounds
  • Fluorenes
  • Chlorodiphenyl (54% Chlorine)
  • fluoranthene