The essential toxin: impact of zinc on human health

Abstract

Compared to several other metal ions with similar chemical properties, zinc is relatively harmless. Only exposure to high doses has toxic effects, making acute zinc intoxication a rare event. In addition to acute intoxication, long-term, high-dose zinc supplementation interferes with the uptake of copper. Hence, many of its toxic effects are in fact due to copper deficiency. While systemic homeostasis and efficient regulatory mechanisms on the cellular level generally prevent the uptake of cytotoxic doses of exogenous zinc, endogenous zinc plays a significant role in cytotoxic events in single cells. Here, zinc influences apoptosis by acting on several molecular regulators of programmed cell death, including caspases and proteins from the Bcl and Bax families. One organ where zinc is prominently involved in cell death is the brain, and cytotoxicity in consequence of ischemia or trauma involves the accumulation of free zinc. Rather than being a toxic metal ion, zinc is an essential trace element. Whereas intoxication by excessive exposure is rare, zinc deficiency is widespread and has a detrimental impact on growth, neuronal development, and immunity, and in severe cases its consequences are lethal. Zinc deficiency caused by malnutrition and foods with low bioavailability, aging, certain diseases, or deregulated homeostasis is a far more common risk to human health than intoxication.

Keywords: essential trace element; toxicity; zinc.

Figure 1.

Cellular zinc homeostasis and its impact on cytotoxicity (A) Cellular zinc homeostasis is mediated by three main mechanisms. First, by transport through the plasma membrane by importers from the Zip-family, and export proteins from the ZnT-family. Second, by zinc-binding proteins such as metallothionein. Third, by transporter-mediated sequestration into intracellular organelles, including endoplasmic reticulum, Golgi, and lysosomes. Tight control of zinc homeostasis is required for maintenance of cellular viability, whereas deregulation leads to cell death. (B) A particular role in intracellular zinc homeostasis is played by the metallothionein/thionein-system. Free and loosely bound zinc ions are bound by the apo-protein thionein (Tred), to form metallothionein (MT). Elevated levels of free zinc ions can bind to zinc finger structures of the metal-regulatory transcription factor (MTF)-1, thus inducing the expression of thionein. Additionally, oxidation of thiols by reactive oxygen (ROS) or nitrogen (RNS) species triggers the formation of the oxidized protein thionin (Tox) with concomitant release of zinc.

Figure 2.

Comparison of the effects of zinc intoxication versus deficiency. Intoxication by excessive exposure to, or intake of, zinc (left hand side), and deprivation of zinc by malnutrition or medical conditions (right hand side), have detrimental effects on different organ systems. Effects that could not be attributed to a certain organ system or affect several organs are classified as systemic symptoms.