Human exposure to arsenic (As) can lead to oxidative stress that can become evident in organs such as the skin, liver, kidneys and lungs. Several intracellular antioxidant defense mechanisms including glutathione (GSH) and metallothionein (MT) have been shown to minimize As cytotoxicity. The current review summarizes the involvement of MT as an intracellular defense mechanism against As cytotoxicity, mostly in blood. Zinc (Zn) and selenium (Se) supplements are also proposed as a possible remediation of As cytotoxicity. In vivo and in vitro studies on As toxicity were reviewed to summarize cytotoxic mechanisms of As. Intracellular antioxidant defense mechanisms of MT are linked in relation to As cytotoxicity. Arsenic uses a different route, compared to major metal MT inducers such as Zn, to enter/exit blood cells. A number of in vivo and in vitro studies showed that upregulated MT biosynthesis in blood components are related to toxic levels of As. Despite the cysteine residues in MT that aid to bind As, MT is not the preferred binding protein for As. Nonetheless, intracellular oxidative stress due to As toxicity can be minimized, if not eliminated, by MT. Thus MT induction by essential metals such as Zn and Se supplementation could be beneficial to fight against As toxicity.
Toxic heavy metals, toxic organic compounds, reactive oxygen species (ROS), infections, and temperature are well-known metallothionein (MT) inducers in human blood. The current review aims to summarize synthesis, function, and fate of human blood MT in response to the known MT inducers. Part of the MTs that are synthesized in different organs such as the liver, kidney, and spleen is transported and stored in different blood cells and in plasma. Cells of the circulatory system also synthesize MT. From the circulation, MT returns to the kidney where the metal-bound MTs are degraded to release the metal ion that in turn induces MT expression therein. The blood MTs play important roles in metal detoxification, transportation, and storage. By neutralizing ROS, MTs protect blood cells from oxidative stress-induced cytotoxicity and genotoxicity. Arguably, MTs are also involved in immune suppression. Given the permeating distribution of blood MT throughout the body as well as its diverse role in the protection against harmful environmental factors and in metal homeostasis, MT could be better recognized as a major public health protein.
At childbirth (parturition), zinc (Zn) homeostasis in cord blood (CB) can be affected by a number of factors: Zn in maternal blood, parturition related stress as well as metallothionein (MT). Both Zn and stress are known inducers of MT which is primarily involved in Zn homeostasis. This study analyzed Zn concentration [Zn], in CB components and MT-2A transcription in CB mononuclear cells (MNC) in relation to primiparous and multiparous childbirth. [Zn] in CB (n = 47) plasma, erythrocytes, and MNCs were measured by atomic absorption spectrophotometry (λ = 213.9 nm). The MT-2A transcription in CB-MNC was quantified using real-time PCR. Significant correlations (Pearson r) were found between: plasma-[Zn] and erythrocyte-[Zn] (p = 0.002); [Zn] and MT-2A messenger RNA (mRNA) (p = 0.000) in CB-MNC. Student's t tests showed higher levels of MT-2A mRNA and MNC-[Zn] in CB of older (≥25 years) compared to younger mothers (≤24 years) (p = 0.043 and p = 0.016, respectively). Significantly higher [Zn] was found in CB plasma (p = 0.017) and MNC (p = 0.041) of older primiparous compared to the younger primiparous and older multiparous mothers respectively. MT-2A mRNA in CB-MNC was significantly lower in CB of younger primiparous mothers compared to their older counterparts (p = 0.001). Path analysis showed that MNC-[Zn] (β = 0.83; p = 0.000) had a greater influence on MT-2A mRNA expression, compared to parity (β = -0.14; p = 0.033). Higher [Zn] in CB of primiparous mothers could be linked to higher stress during parturition, however, might be beneficial for the growth and development of the child. Together MNC-[Zn] and parity contributed ~70 % of the MT-2A transcription in CB-MNC.