THE MUTAGENICITY OF THE TYROSINE METABOLITE, FUMARYLACETOACETATE, IS ENHANCED BY GLUTATHIONE DEPLETION

The toxicity of tyrosine metabolites has been suggested, but not prove n, to play a role in the ethiopathogenesis of hepatic alterations obse rved in hereditary tyrosinemia type I(HT I), a metabolic disease cause d by a deficiency of the last enzyme in the tyrosine catabolic pathway , fumarylacetoacetate hydrolase. One of these metabolites, fumarylacet oacetate (FAA), is mutagenic in Chinese hamster V79 cells. We report h ere that FAA is a powerful glutathione depletor in this cell system. M oreover, the mutagenicity of FAA (100 mu M) is potentiated by depletio n 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. T his enhancement is abolished by a partial replenishment of intracellul ar glutathione (32% of control levels) prior to FAA treatment. Reactiv e oxygen species are not generated during FAA treatment of glutathione -depleted or undepleted cells. Although the mechanism(s) underlying th e mutagenic activity of FAA remains to be identified, these results sh ow that the glutathione depletion activity of FAA may play an importan t role in the manifestation of its mutagenicity which likely contribut es to the HT I-associated liver pathologies. (C) 1997 Academic Press.