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

Raney KD, Meyer DJ, Ketterer B, Harris TM, Guengerich FP
Chem Res Toxicol. 1992 5 (4): 470-8

PMID: 1391613 · DOI:10.1021/tx00028a004

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)

MeSH Terms (16)

Aflatoxin B1 Animals Catalysis Cytosol Glutathione Glutathione Transferase Humans In Vitro Techniques Liver Magnetic Resonance Spectroscopy Male Mice Rats Rats, Sprague-Dawley Stereoisomerism Sulfhydryl Compounds

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