Kinetic and Therapeutic Aspects of Zinc Metabolism

Zinc is one of the essential trace elements for man and there is now considerable evidence to show that a deficiency of zinc is related to the poor wound healing found in some patients, particularly those with varicose ulcers. Oral zinc therapy has been used successfully in the treatment of these patients but as zinc is toxic in large doses many workers have regarded it with disfavour, particularly since little is known about the metabolism of either dietary or therapeutic doses of zinc in man. The aim of the present work has therefore been to study the manner in which both trace and therapeutic amounts of zinc are transported by plasma to the organs and tissues and to relate the uptake and clearance of zinc from plasma to that of the various tissues. An initial study was carried out on in vitro binding of zinc to the plasma proteins to compare the results obtained using protein separation by electrophoresis on cellulose acetate and by chromatography using Sephadex gels. Chromatography on Sephadex gels was found to be the more suitable method, particularly for study of endogenous zinc binding and of the binding of trace amounts of radiozinc administered to subjects in vivo. While albumin was found to bind virtually all the zinc added to plasma in vitro, the endogenous pattern of zinc binding has two main components, albumin and a second high molecular weight protein fraction coincident with alpha2-macroglobulin, which has been shown to be a zinc metalloprotein by other workers. A study of the endogenous zinc distribution in normal subjects shoved that approximately one third of the plasma zinc was bound to alpha2-macroglobulin and the remaining two thirds to albumin. The variation of binding of a tracer dose of radiozinc administered orally to two normal volunteers was studied as a function of time. It was found that at peak plasma zinc-65 level about 90% of the zinc-65 was bound to albumin but this level dropped during the first 2k hours to about 75%, a value approximately equal to the endogenous proportion. When intravenous clearance of zinc-65 was studied it was found that the major part of the zinc-65 disappeared very rapidly from plasma, with a half-life of about 20 minutes. As this could be related to clearance from the albumin fraction it was shown that albumin is a transport protein for zinc. When the uptake of zinc-65 by liver and muscle was compared with the disappearance of zinc from plasma it was found that the zinc-65 was cleared very rapidly into the liver during the first 2k hours, at a rate which corresponded to the clearance of zinc-65 from the albumin fraction. Clearance of zinc-65 in plasma into the liver stopped when the fraction of the zinc-65 bound to alpha2-macroglobulin reached about one third of the total. Uptake by muscle was much slower and evidence has been produced to show that this is due to transfer of zinc from liver to muscle by plasma. The clearance of a therapeutic dose of zinc from plasma was then studied in normal volunteers after an oral dose of zinc sulphate. It was found that the resultant increase in plasma zinc was bound to both alpha2-macroglobulin and albumin fractions, in some cases more than doubling the original amounts bound to the proteins. After about 6 hours both albumin and alpha2-macroglobulin zinc levels had dropped significantly, in some cases back to the original levels, showing that alpha2-macroglobulin also a transport protein for zinc. There are thus two transport proteins for zinc, albumin and alpha2-macroglobulin, which apparently have separate functions in the control and clearance of absorbed zinc to the tissues