The Mutagenicity of the Tyrosine Metabolite, Fumarylacetoacetate, Is Enhanced by Glutathione Depletion

doi:10.1006/bbrc.1997.6220

Biochemical and Biophysical Research Communications

Volume 232, Issue 1, 6 March 1997, Pages 42-48

https://doi.org/10.1006/bbrc.1997.6220 Get rights and content

Abstract

The toxicity of tyrosine metabolites has been suggested, but not proven, to play a role in the ethiopathogenesis of hepatic alterations observed in hereditary tyrosinemia type I (HT I), a metabolic disease caused by a deficiency of the last enzyme in the tyrosine catabolic pathway, fumarylacetoacetate hydrolase. One of these metabolites, fumarylacetoacetate (FAA), is mutagenic in Chinese hamster V79 cells. We report here that FAA is a powerful glutathione depletor in this cell system. Moreover, the mutagenicity of FAA (100 μM) is potentiated by depletion of cellular glutathione (12% of control levels) by pretreatment with L-buthionine-(S,R)-sulphoximine. In this case, the mutation frequency induced by FAA is 10 times higher than in untreated, control cells. This enhancement is abolished by a partial replenishment of intracellular glutathione (32% of control levels) prior to FAA treatment. Reactive oxygen species are not generated during FAA treatment of glutathione-depleted or undepleted cells. Although the mechanism(s) underlying the mutagenic activity of FAA remains to be identified, these results show that the glutathione depletion activity of FAA may play an important role in the manifestation of its mutagenicity which likely contributes to the HT I-associated liver pathologies.

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^☆: Abbreviations used: HT I, hereditary tyrosinemia type IFAH, fumarylacetoacetate hydrolase; FAA, fumarylacetoacetate; MAA, maleylacetoacetate; SA, succinylacetone GSH, glutathione; GSSG, glutathione disulfide; DEM, diethylmaleate; BSO, L-buthionine-(S,R)-sulphoximine; HBSS, Hank's balanced salt solution; GSH-MEE, GSH monoethyl ester; HGPRT, hypoxanthine-guanine phosphoribosyl transferase; ROS, reactive oxygen species; DCF-DA, 2′,7′-dichlorofluorescin diacetate; DCF, 2′,7′-dichlorofluorescein;

^☆☆: C. R. ScriverA. L. BeaudetW. S. SlyD. Valle, Eds.

¹: Corresponding author. Fax: (418) 656-7176. E-mail: robert. [email protected].

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Regular ArticleThe Mutagenicity of the Tyrosine Metabolite, Fumarylacetoacetate, Is Enhanced by Glutathione Depletion☆,☆☆

Abstract

J. Pediatr.

Mutation Res.

J. Immunol. Methods

J. Biol. Chem.

Methods Enzymol.

J. Biol. Chem.

Methods Enzymol.

Mutation Res.

Proc. Natl. Acad. Sci. USA

Am. J. Hum. Genet.

J. Clin. Invest.

Pediatr. Res.

Regular Article
The Mutagenicity of the Tyrosine Metabolite, Fumarylacetoacetate, Is Enhanced by Glutathione Depletion☆,☆☆