An Overview of Carcinogenic Heavy Metal: Molecular Toxicity Mechanism and Prevention

Abstract

Almost all heavy metals are serious toxicants as carcinogens. However, due to their chemical and physiological properties, heavy metals are useful in industrial areas including alloy, smelting and production of commercial products. Such applications increase the opportunity for heavy metal exposure. Waste from industrial processes is also a major source of environmental contamination and accumulation in the human body. Arsenic, cadmium, chromium, and nickel are classified as group 1 carcinogens by the International Agency for Research on Cancer, and are utilized commercially. In this review, we used molecular pathway analysis to understand the toxicity and carcinogenic mechanisms of these metals. Our analyzed data showed that above-mentioned metallic substances induce oxidative stress, DNA damage, and cell death processes, resulting in increase the risk of cancer and cancer-related diseases. Thus, we might think phytochelatin molecules and antioxidative phytochemical substances are helpful for prevention of heavy metal-induced cancer.

Keywords: Cancer prevention; Carcinogenic heavy metals; Molecular mechanism; Pathway analysis.

Figure 1.

Pathway analysis of arsenic toxicity. The analyzed data showed the potentials of genomic interaction, cellular processes, and diseases induced by exposure of arsenic. Ten proteins, 5 cellular processes, 8 diseases and 2 small molecules appeared in figure. GSTO, glutathione-S-transferase omega; C10orf32, chromosome 10 open reading frame 32; IFNG, interferon gamma; CAT, catalase; CDKN2B, cyclin-dependent kinase 4 inhibitor 2B; TP53, tumor protein 53; CD14, monocyte differentiation antigen CD14; GYPA, glycophorin-A; PNP, purine nucleoside phosphorylase.

Figure 2.

Pathway analysis of cadmium toxicity. The analyzed data showed the potentials of genomic interaction, cellular processes, and diseases induced by exposure of cadmium. Ten proteins, 5 cellular processes, 13 diseases, 2 small molecules and 1 functional class appeared in figure. YAP1, yes-associated protein 1; HTT, huntingtin; BAX, B cell lymphoma 2 protein-associated X protein; ROS, reactive oxygen species; ESR1, estrogen receptor 1; MAPK1, mitogen-activated protein kinase 1; ABCB1, aTP-binding cassette sub-family B member 1; MT2A, metallothionein 2A; SLC11A2, solute carrier family 11, member 2; MT1A, metallothionein 1A; SLC30A1, solute carrier family 30, member 1.

Figure 3.

Pathway analysis of chromium toxicity. The analyzed data showed the potentials of genomic interaction, cellular processes, and diseases induced by exposure of chromium. 12 proteins, 5 cellular processes, 13 diseases, 2 small molecules and 1 functional class appeared in figure. MAPK, mitogen-activated protein kinase; AKT1, V-akt murine thymoma viral oncogene homolog 1; NFE2L2, nuclear factor, erythroid 2-like 2; CAT, catalase; IFNG, interferon gamma; CASP3, caspase 3, apoptosis-related cysteine peptidase; VEGFA, vascular endothelial growth factor A; TP53, tumor protein 53; BAX, B cell lymphoma 2 protein-associated X protein; ROS, reactive oxygen species.

Figure 4.

Pathway analysis of nickel toxicity. The analyzed data showed the potentials of genomic interaction, cellular processes, and diseases induced by exposure of nickel. 15 proteins, 8 cellular processes, 15 diseases, 1 small molecule and 1 functional class appeared in figure. ROS, reactive oxygen species; TLR4, toll-like receptor 4; MAPK, mitogen-activated protein kinase; NDRG1, N-myc downstream regulated 1; CAT, catalase; TP53, tumor protein 53; ICAM1, Intercellular adhesion molecule 1; JUN, Jun proto-oncogene; SERPINE1, serine peptidase inhibitor, clade E, member 1; IL, interleukin; BCL2, B cell lymphoma 2 protein; FOS, Finkel-Biskis-Jinkins murine osteosarcoma viral oncogene homolog; CDH1, cadherin 1.

Figure 5.

Mechanism of heavy metal detoxification via phytochelatin (PC) and antioxidants. (A) Schematic diagram of the PC pathway. Ionized forms of heavy metals are in bold circles marked as ‘MET-ion’. PCs molecules are in bold circles marked as ‘PCs’. A double-lined arrow indicates import direction. A bold arrow indicates the PCs synthesis process. Enzymes are written in an italicized bold font. (B) Schematic diagram of heavy metal-induced antioxidant processes. ROS generation by heavy metal exposure activates Nrf2, which is a transcription factor for antioxidant response elements (AREs). Phytochemicals contribute to antioxidative process via stimulation of the Nrf2 pathway. Various antioxidants are activated and remove ROS. GSH, glutathione; ROS, reactive oxygen species; SOD, superoxide dismutase; NQO1, NAD(P)H: quinone acceptor oxidoreductase 1; HO-1, heme oxygenase 1.