title: The mutagenicity of the tyrosine metabolite, fumarylacetoacetate, is enhanced by glutathione depletion.
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 microM) 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.
authors.affiliation: Laboratoire de Génétique Cellulaire et Développementale, RSVS, Pavillon Marchand, Université Laval, Ste-Foy, Quebec, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Jorquera
authors.forename: R M
authors.initials: RM
authors.lastname: Tanguay
mesh_terms: D000090:Acetoacetates / Q000633:toxicity*; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D005978:Glutathione / Q000378:metabolism*; D009153:Mutagens / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D000090:Acetoacetates; D009153:Mutagens; D017382:Reactive Oxygen Species; C105171:fumarylacetoacetate; D014443:Tyrosine; D005978:Glutathione