The presence of nonessential metals like arsenic (As) and cadmium (Cd) in the environment is prevalent. Since these metals are highly toxic, they pose a considerable threat to nature and to human health. The main routes of poisoning are through occupational exposure or through ingestion of contaminated food and water. Pollution of soils with toxic agents is a common global problem, and contamination of drinking water by arsenic is a major health concern because of the large number of contaminated sites and people at risk. These metals are implicated in a broad spectrum of degenerative conditions in humans, including neurotoxicity, nephrotoxicity, genotoxicity and carcinogenesis. For example, chronic As exposure induces cardiovascular diseases, neurological disorders and liver injury, and is associated with cancers of the skin, bladder, liver and lung. Cd is considered genotoxic and carcinogenic for lung, kidney and prostate [1
]. The International Agency for Research on Cancer (IARC) classifies both metals as group I carcinogens [5
The toxicity mechanisms of As and Cd are not fully understood at the molecular level. In general, they may act by targeting signalling or regulatory proteins that control cell proliferation, differentiation and cell cycle regulation. Although the mode of action of each metal is likely to involve unique features, some toxicity mechanisms may be shared. Similarly, cells may mount both common and metal-specific responses to counteract toxicity [2
]. A common property of As and Cd is their high reactivity with sulphhydryl groups. Hence, they can bind to and affect the activity of many proteins. In addition, these metals are known to generate oxidative stress in cells and their toxicity has partly been attributed to their capability to induce formation of reactive oxygen species (ROS). The damage caused by ROS to lipids, proteins and DNA are likely to contribute to As and Cd toxicity [7
]. Nevertheless, neither the exact details of metal-induced ROS generation nor the full set of toxicity targets is known.
Drugs containing arsenicals are currently used in medical treatment. The arsenic-containing drug melarsoprol®
is used to treat diseases caused by the protozoan parasite Trypanosoma
], whereas arsenic trioxide (Trisenox®
) is used as a treatment for acute promyelocytic leukaemia and it may also be employed for other haematological and solid cancers [12
]. However, the emergence of resistance threatens the efficacy of medical treatment [13
] and hence, there is an increasing demand to identify tolerance mechanisms. Similarly, the prospect of using plants to clean up polluted soils has recently attracted considerable attention. Nevertheless, to develop phytoremediation into a useful approach requires a detailed understanding of the genetics and molecular basis of detoxification and tolerance acquisition [14
Tolerance and detoxification mechanisms often involve extrusion of the toxic ions from the cell, sequestration within internal organelles, chelation by metal-binding proteins, and reduction of uptake. Common to these systems is that they reduce the cellular content of the toxic agent, although their molecular basis may differ between metals and also between organisms [16
]. Furthermore, it is clear that not only the detoxification systems themselves, but also the proteins that regulate their expression, localization and/or activity will contribute to cellular metal tolerance.
The aim of this work was to provide a global view of the genetic basis of As and Cd toxicity and detoxification by identifying the molecular/cellular targets of their action and to reveal tolerance acquisition mechanisms. Unveiling metal toxicity and tolerance mechanisms in yeast may prove of value for identifying similar mechanisms in higher eukaryotes.