INVOLVEMENT OF OXIDATIVE STRESS IN PARAQUAT-INDUCED METALLOTHIONEIN SYNTHESIS UNDER GLUTATHIONE DEPLETION

The inhibition of glutathione (GSH) synthesis by L-buthionine-SR-sulfo ximine (BSO) causes aggravation of hepatotoxicity of paraquat (PQ), an oxidative-stress inducing substance, in mice, On the other hand, synt hesis of metallothionein (MT)I a cysteine-rich protein having radical scavenging activity, is induced by PQ, and the induction by PQ is sign ificantly enhanced by pretreatment of mice with BSO. The purpose of pr esent study is to examine whether generation of reactive oxygens is in volved in the induction of MT synthesis by PQ under inhibition of GSH synthesis. Administration of PQ to BSO-pretreated mice increased hepat ic lipid peroxidation and frequency of DNA single strand breakage foll owed by manifestation of the liver injury and induction of MT synthesi s. Both vitamin E and deferoxamine prevented MT induction as well as l ipid peroxidation in the liver of mice caused by administration of BSO and PQ, In cultured colon 26 cells, both cytotoxicity and the increas e in MT mRNA level caused by PQ were significantly enhanced by pretrea tment with BSO. Facilitation of PQ-induced reactive oxygen generation was also observed by BSO treatment. These results suggest that reactiv e oxygens generated by PQ under inhibition of GSH synthesis may stimul ate MT synthesis. GSH depletion markedly increased reactive oxygen gen eration induced by PQ, probably due to the reduced cellular capability to remove the radical species produced. (C) 1998 Elsevier Science Inc .