Copper and zinc metabolism in health and disease: speciation and interactions.

It has long been evident that the metabolism of trace elements cannot be considered in isolation. A wide range of nutritional and physiological factors can influence their uptake, transport and storage, with subsequent enhancement of susceptibility to deficiency or toxicity states. Interactions occur with other trace elements and these can be classified as competitive or non-competitive, direct or indirect. However, their physiological or toxicological significance is sometimes debatable, partly because they were demonstrated under extreme experimental conditions where massive doses of the antagonistic metal were administered, often by parenteral routes and to animals whose trace element status was already severely compromised. Our understanding of the mechanisms of the interactions is frequently limited and indeed in only a few cases has it been possible to describe these on a molecular basis. It is almost traditional to cite the early work of Hill & Matrone (1970) as the first serious attempt to describe trace element interactions on a rational basis. They postulated that elements with similar physical or chemical properties will act antagonistically to each other biologically. The implication was that such metals could compete for binding sites on transport proteins or on enzymes requiring metals as co-factors. Over subsequent years, much evidence was produced in support of this view but rarely was the specific site of interaction identified, other than at tissue level. In part this reflected somewhat embarrassing limitations in our knowledge of the proteins involved in the intracellular and extracellular transport and storage of trace metals.