Aerobic organisms have to maintain a reduced cellular redox environment in the face of the prooxidative conditions of aerobic life. The incomplete reduction of oxygen to water during respiration leads to the formation of redox-active oxygen intermediates such as the superoxide anion radical (O 2 . ), hydrogen peroxide (H 2 O 2 ), and the hydroxyl radical (for review see Refs.

Cadmium is very toxic at low concentrations, but the basis for its toxicity is not clearly understood. We analyzed the proteomic response of yeast cells to acute cadmium stress and identified 54 induced and 43 repressed proteins. A striking result is the strong induction of 9 enzymes of the sulfur amino acid biosynthetic pathway. Accordingly, we observed that glutathione synthesis is strongly increased in response to cadmium treatment. Several proteins with antioxidant properties were also induced. The induction of nine proteins is dependent upon the transactivator Yap1p, consistent with the cadmium hypersensitive phenotype of the YAP1-disrupted strain. Most of these proteins are also overexpressed in a strain overexpressing Yap1p, a result that correlates with the cadmium hyper-resistant phenotype of this strain. Two of these Yap1p-dependent proteins, thioredoxin and thioredoxin reductase, play an important role in cadmium tolerance because strains lacking the corresponding genes are hypersensitive to this metal. Altogether, our data indicate that the two cellular thiol redox systems, glutathione and thioredoxin, are essential for cellular defense against cadmium.Heavy metals represent major environmental hazards to human health. In particular, cadmium is very toxic and probably carcinogenic at low concentrations. However, the biological effects of this metal and the mechanism of its toxicity are not yet clearly understood. It has been proposed that Cd 2ϩ ions might displace Zn 2ϩ and Fe 2ϩ in proteins (1), resulting in their inactivation and in the release of free iron, which might generate highly reactive hydroxyl radicals (OH ⅐ ) (2). In support of this hypothesis, a major effect of cadmium is oxidative stress (3), particularly lipid peroxidation (1). However, it is not known whether these effects are responsible for the extreme toxicity of the metal.Living organisms use several mechanisms to counter cadmium toxicity. In bacteria, efflux pumps are able to export toxic ions outside the cell (4). In higher eukaryotes, Cd 2ϩ is sequestered by metallothioneins through their high cysteine content (5). Cadmium can also be detoxified by chelation to GSH or to phytochelatin, a glutathione polymer of general structure (␥-Glu-Cys) n -Gly synthesized from GSH in plants and in the yeast Schizosaccharomyces pombe. Cd 2ϩ -phytochelatin and Cd 2ϩ ⅐ (GSH) 2 complexes are transported into the vacuole by ATPbinding cassette transporters (6 -8).Yap1p and Skn7p are yeast transcription factors that regulate the adaptive response to oxidative stress (9 -11). Strains lacking either transcription factor are sensitive to H 2 O 2 and are defective in the induction by H 2 O 2 of several enzymes with antioxidant properties (9). Yap1p is also important in cadmium tolerance because yap1-deleted strains are very sensitive to cadmium, and strains overexpressing YAP1 are hyper-resistant to this toxic metal (12). The contribution of Skn7p to the cadmium response is more complex, because skn7-deleted strains are hyper-resistant to cadmium (9)...