Evidence for operation of the direct zinc ligand exchange mechanism for trafficking, transport, and reactivity of zinc in mammalian cells

Abstract

In addition to its critical role in normal cell function, growth, and metabolism, zinc is implicated as a major factor in the development and progression of many pathological conditions and diseases. Despite this importance of zinc, many important factors, processes, and mechanisms of the physiology, biochemistry, and molecular biology of zinc remain unknown. Especially important is the unresolved issue regarding the mechanism and process of the trafficking, transport, and reactivity of zinc in cells; especially in mammalian cells. This presentation focuses on the concept that, due to the existence of a negligible pool of free Zn2+ ions in the mammalian cell environment, the trafficking, transport and reactivity of zinc occurs via a direct exchange of zinc from donor Zn-Ligands to acceptor ligands. This Zn exchange process occurs without the requirement for production of free Zn2+ ions. The direct evidence from mammalian cell studies is presented in support of the operation of the direct Zn-Ligand exchange mechanism. The paper also provides important information and conditions that should be considered and employed in the conduct of studies regarding the role and effects of zinc in biological/biomedical research; and in its clinical interpretation and application.

The status of zinc in the development of hepatocellular cancer

“…The process and factors involved are complex and still largely unknown and speculative. We refer the reader to our reviews 17,23 for extensive description of zinc relationships in mammalian cells. The total zinc concentration of mammalian cells is first dependent upon the cellular uptake of zinc from its extracellular environment.…”

Metallothionein 1G and Zinc Sensitize Human Colorectal Cancer Cells to Chemotherapy

“…Free zinc ions exist in the picomolar range and may be considered negligible due to tight regulation by zinc transporters, MTs, and organelle sequestration (16). Intracellular zinc pools consist mainly of tightly bound, unexchangeable zinc bound to proteins (the "immobile" pool), and of the exchangeable, loosely bound zinc termed the "labile" pool, which is complexed to low molecular weight ligands and MTs (17). The latter represents about 5% of the total intracellular zinc and participates in zinc transfer reactions and signaling.…”

Zinc exposure for female workers in a galvanizing plant in Northern Italy

“…In other words, even the relatively low amount of zinc absorbed through both respiratory and gastrointestinal system in a setting of reduced occupational exposure may eventually result in transient high serum zinc concentration, that elicits an increased urinary excretion in order to avoid an excessive increase of body stores. Unfortunately, there is no clear correlation between absorbed dose and excreted amount of zinc: its rate is dependent on both current and past intakes, probably in dynamic equilibrium with body stores [20,21,[24][25][26][27]. However, several limitations within our study should be addressed.…”

“…Around 98% of serum zinc is bound to proteins (in particular: 85% to albumin, 12% to α 2 -macroglobulin) whereas the remainder 2% is bound to ultrafiltereable small organic molecules such as citrate and amino-acids. As the latter is only excreted in the urine, usual urinary levels range from 25 μg/dl to 65 μg/dl (or 0.5 mg/g creatinine) [20,21,[24][25][26][27]. Toxicokinetics of inhaled zinc still remains largely undefined.…”