In mammalian cultured cells, the activity of a cystine/glutamate transporter, designated System x, has been shown to be essential for maintaining intracellular glutathione levels and the extracellular cystine/cysteine redox balance. The substrate-specific subunit of this transporter, xCT, is strongly induced by various stimuli, including oxidative stress, which suggests that xCT is one of the adaptive cellular defense systems against these types of stress. Embryonic fibroblasts from xCT-deficient mice fail to survive unless a cysteine precursor, N-acetylcysteine, is present. However, it is unclear whether xCT has similar functions in vivo because xCT-deficient mice are apparently normal. In this study, we investigated the phenotype of the xCT-deficient mice under paraquat-induced oxidative stress. At a paraquat dose of 45 mg/kg, the survival rate of the xCT-deficient mice was significantly lower than that of the wild-type mice. Under this condition, total glutathione (the reduced form of glutathione (GSH)+ the oxidized form of GSH) levels in the lungs of the xCT-deficient mice were lower than those in the lungs of the wild-type mice. Histopathological examinations showed that paraquat administration worsened the alveolar structure of the xCT-deficient mice compared with the wild-type mice. After paraquat treatment, obvious 8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal reactivity was detected in the lungs of the xCT-deficient mice. Although xCT expression was slightly detectable in the lungs of the normal wild-type mice, paraquat administration induced xCT mRNA expression in the lung. Constitutive expression of xCT mRNA was detected in alveolar macrophages isolated from the pulmonary lavage fluid of the wild-type mice, and paraquat administration strongly enhanced xCT mRNA expression in these cells. GSH levels in bronchoalveolar lavage fluid were significantly higher in the paraquat-treated wild-type mice than in the paraquat-treated xCT-deficient mice. These results suggest that xCT contributes to the maintenance of glutathione levels in lungs and the glutathione redox state as a protective system against paraquat toxicity in vivo. (C) 2012 Elsevier Inc. All rights reserved.