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

Abstract

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. C 0 P P E R-Z I N C I N 'T E R ACT I 0 N S The mutual antagonism between Zn and Cu has been regarded as a prime example of competitive biological interactions between metals with similar chemical and physical properties. This has been demonstrated in many investigations in a range of species. Thus, excessive Zn supply has been shown to inhibit intestinal absorption, hepatic accumulation and placental transfer of Cu, as well as to induce clinical and biochemical signs of Cu deficiency (Bremner et af. 1976; Hall et af. 1979; L'Abbe & Fischer, 1984; Yardick et af. 1989). The situation regarding the reverse interaction, namely the effects of Cu on Zn metabolism, has been less clear. Excessive Cu supply can affect hepatic Zn metabolism in some species but there is no consistent evidence that Zn absorption is seriously affected (Hall et af. 1979; Blalock et af. 1988). This casts some doubt on the mutuality of the interaction. Most of the early investigations were largely descriptive and they did little to elucidate the precise molecular basis or locus of the interaction. Cu and Zn occupy a similar part of the periodic table, the Zn2+ and Cuf ions being isoelectronic and having similar ionic radii. Both metals readily form chelates with 0-, S-, or N-containing ligands but not always with the same stereochemical arrangement of bonds. However, unlike Zn which occurs in only one valency state, Cu can occur in two, as Cu+ and Cu2+; indeed there have been suggestions that Cu3+ may also have a