Glutathione conjugation of aflatoxin B1 exo- and endo-epoxides by rat and human glutathione S-transferases

Chem Res Toxicol. Jul-Aug 1992;5(4):470-8. doi: 10.1021/tx00028a004.

Abstract

Much evidence supports the view that the rate of conjugation of glutathione (GSH) with aflatoxin B1 (AFB1) exo-epoxide is an important factor in determining the species variation in risk to aflatoxins and that induction of GSH S-transferases can yield a significant protective effect. An assay has been developed in which the enzymatic formation of the conjugates of GSH and AFB1 exo-epoxide and the recently described AFB1 endo-epoxide is measured directly. 1H NMR spectra are reported for both the AFB1 exo- and endo-epoxide-GSH conjugates. Structural assignments were made by comparison with AFB1 exo- and endo-epoxide-ethanethiol conjugates, for which nuclear Overhauser effects were measured to establish relative configurations. The endo-epoxide was found to be a good substrate for GSH conjugate formation in rat liver cytosol while mouse liver cytosol conjugated the exo-epoxide almost exclusively. Human liver cytosol conjugated both epoxide isomers to much lower extents than did cytosols prepared from rats or mice. Purified rat GSH S-transferases catalyzed the formation of the AFB1 exo-epoxide-GSH conjugate in the order 1-1 approximately 4-4 approximately 3-3 greater than 2-2 greater than 4-6 (7-7 and 8-8 did not form the exo-epoxide-GSH conjugate at levels above the nonenzymatic rate). The only rat GSH S-transferases that conjugated the endo-epoxide were 4-4 and 4-6, with 4-4 being the more active.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication types

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

MeSH terms

  • Aflatoxin B1 / analogs & derivatives*
  • Aflatoxin B1 / chemical synthesis
  • Aflatoxin B1 / metabolism
  • Animals
  • Catalysis
  • Cytosol / enzymology
  • Glutathione / analogs & derivatives
  • Glutathione / chemical synthesis
  • Glutathione / metabolism*
  • Glutathione Transferase / metabolism*
  • Humans
  • In Vitro Techniques
  • Liver / enzymology
  • Magnetic Resonance Spectroscopy
  • Male
  • Mice
  • Rats
  • Rats, Sprague-Dawley
  • Stereoisomerism
  • Sulfhydryl Compounds / chemistry

Substances

  • Sulfhydryl Compounds
  • aflatoxin B1-2,3-oxide
  • Aflatoxin B1
  • Glutathione Transferase
  • Glutathione
  • ethanethiol