The role of oxidative stress in carcinogenesis induced by metals and xenobiotics

Abstract

In addition to a wide range of adverse effects on human health, toxic metals such as cadmium, arsenic and nickel can also promote carcinogenesis. The toxicological properties of these metals are partly related to generation of reactive oxygen species (ROS) that can induce DNA damage and trigger redox-dependent transcription factors. The precise mechanisms that induce oxidative stress are not fully understood. Further, it is not yet known whether chronic exposures to low doses of arsenic, cadmium or other metals are sufficient to induce mutations in vivo, leading to DNA repair responses and/or tumorigenesis. Oxidative stress can also be induced by environmental xenobiotics, when certain metabolites are generated that lead to the continuous release of superoxide, as long as the capacity to reduce the resulting dions (quinones) into hydroquinones is maintained. However, the specific significance of superoxide-dependent pathways to carcinogenesis is often difficult to address, because formation of DNA adducts by mutagenic metabolites can occur in parallel. Here, we will review both mechanisms and toxicological consequences of oxidative stress triggered by metals and dietary or environmental pollutants in general. Besides causing DNA damage, ROS may further induce multiple intracellular signaling pathways, notably NF-kB, JNK/SAPK/p38, as well as Erk/MAPK. These signaling routes can lead to transcriptional induction of target genes that could promote proliferation or confer apoptosis resistance to exposed cells. The significance of these additional modes depends on tissue, cell-type and is often masked by alternate oncogenic mechanisms being activated in parallel.

Figure 1

Carcinogenic mechanisms of arsenic compounds. Inorganic arsenic compounds and methylated metabolites display similar genotoxic properties. Generation of oxidative stress is regarded as central mechanism in As-mediated carcinogenesis. However, the precise mechanisms of ROS-formation are not yet clarified. A mitochondria-dependent mechanism and a H₂O₂/hydroxy radical pathway are discussed. In addition, arsenic affects DNA methylation and DNA repair enzymes (see text for details).

Figure 2

Carcinogenic mechanisms of chromium compounds. Chromium (VI) compounds are internalized in cells via anionic channels. Cr(VI) is then reduced and accumulates as trivalent ion. Formation of Cr(III)-DNA adducts is regarded as predominant carcinogenic mechanism (see text for details). In parallel, chromium ions can engage in Fenton-like reactions, generating hydroxy radicals. However, molecular details of these reactions need still to be clarified. The overall relevance of oxidative stress for chromium mediated carcinogenesis remains controversial.

Figure 3

Carcinogenic mechanisms of nickel. Nickel ions can induce oxidative stress, which provides a primary genotoxic stimulus required for carcinogenesis (red lines). In addition, Ni(II) triggers multiple mechanisms that can amplify the moderate effects of oxidative stress (plus sign, ). An interplay of enhanced proliferation and up-regulation of p53 could constitute a strong selective pressure, favouring mutations, which may inactivate tumor suppressor genes (see text for details).

Figure 4

Cadmium and oxidative stress. Cadmium does not belong to redox-active metals. Several mechanisms for generation of ROS have been proposed though (see text for details). Chronic Cd(II) exposure can also induce expression of metallothionin (MT) and triggers adaption mechanisms towards oxidative stress, thus limiting the role of ROS in carcinogenesis. Alternate carcinogenic mechanisms of cadmium, such as inhibition of DNA repair, are not shown in this illustration.

Figure 5

Role of endogenous ROS. Endogenous ROS are second messengers that are utilized by cytokine receptors, as for example tumor necrosis factor (TNF) α receptor 1 (TNFR1) (see text for explanation). The alternate ROS pathway, involving FAN and other signaling activities of TNFR1 are not shown in this illustration. TRADD, TNFR1-associated death domain protein; ASK1, apoptosis signal-regulating kinase 1.