This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Meerman, J. H. N. Articles by Tijdens, R. B. Search for Related Content PubMed PubMed Citation Articles by Meerman, J. H. N. Articles by Tijdens, R. B.

Effect of Glutathione Depletion on the Hepatotoxicity and Covalent Binding to Rat Liver Macromolecules of N-Hydroxy-2-acetylaminofluorene¹

Department of Pharmacology, University of Groningen, Groningen and Center for Biopharmaceutical Sciences, Division of Toxicology, University of Leiden, Leiden, The Netherlands

Glutathione plays an important role in the protection of the liver against several hepatotoxins. The hepatocarcinogen N-hydroxy-2-acetylaminofluorene is converted in the rat in vivo to reactive metabolites that bind covalently to cellular macromolecules. These metabolites may also react with glutathione, resulting in the formation of glutathione conjugates and in the detoxification of reactive metabolites. The role of glutathione in detoxification was investigated by depletion of glutathione in the rat in vivo with diethyl maleate.

When rats were pretreated with diethyl maleate, 45 min before the administration of N-hydroxy-2-acetylaminofluorene, excretion of 2-acetylaminofluorene:glutathione conjugates in bile was decreased by 60% as compared to controls. However, total covalent binding to rat liver protein was not increased, and total binding to DNA was even decreased (p < 0.1), apparently at the expense of the acetylated carcinogen-DNA adducts. Formation of deacetylated, 2-aminofluorene adducts to DNA was not affected by diethyl maleate. Pretreatment with diethyl maleate had no major effect on the acute hepatotoxic effects of N-hydroxy-2-acetylaminofluorene.

The results indicate that glutathione does not play a vital role in the detoxification of reactive metabolites generated from the carcinogen N-hydroxy-2-acetylaminofluorene, since glutathione is not very effective in competing with macromolecules for trapping of reactive metabolites of N-hydroxy-2-acetylaminofluorene. Thus, 1 mM glutathione did not decrease the covalent binding of 2-acetylaminofluorene-N-sulfate (one of the main reactive metabolites that is formed in vivo) to DNA in vitro, while 10 mM glutathione decreased the covalent binding to RNA by only 20% and to DNA by only 40%.

¹ This study was supported by a grant from the Dutch Cancer Foundation (Koningin Wilhelmina Fonds).

² To whom requests for reprints should be addressed, at Center for Biopharmaceutical Sciences, Division of Toxicology, University of Leiden, P.O. Box 9503, 2300 RA Leiden, The Netherlands.

Received 3/20/84. Accepted 11/27/84.