Downloaded from by BhDMf5ePHKbH4TTImqenVA+ lpWIIBvonhQl60EtgtdlLYrLzSPu+ hQedJnbNaXBf on 11/15/2023 balance studies, in which patients were put into a negative copper balance by zinc therapy as a result of high levels of copper excretion in the stool (3, 14, 15). Then, in 1992, we carried out a study of the induction of intestinal cell metallothionein, using intestinal biopsies, by zinc therapy in Wilson’s disease patients (16). We found that with a half-life of about 5–6 days, intestinal metallothionein was induced to high levels by zinc therapy. The state of metallothionein induction correlated nicely with blockade of absorption of orally administered 64-copper, thus supporting the theory that metallothionein induction was the mechanism whereby zinc blocks copper absorption (16). In the present issue of the Journal, Sturniolo et al., who for the past 10 yr or so have been using zinc for the treatment of Wilson’s disease, have added very useful information on zinc induction of intestinal metallothionein in Wilson’s disease (17). These authors used duodenal biopsies, rather than biopsies from the upper small intestine (primarily ileum), which we had used. This adds another region of the small intestine, and may improve uniformity of results. Sturniolo et al.(17) found an average of a 1500-fold increase in metallothionein induction in the duodenum by zinc. This finding assists in the definitive establishment that, after zinc treatment, the small intestinal metallothionein is heavily induced all up and down the small intestine. Sutrniolo et al.(17) also looked at the zinc content of the biopsied duodenum and found that it correlated strongly with metallothionein content. This observation suggests that almost all of the duodenal zinc, after zinc therapy, is bound to metallothionein. This fits nicely with the hypothesis that the major anticopper action of zinc is intestinal metallothionein induction.

Interestingly, the authors find a high duodenal iron in zinc-treated patients, but not the duodenitis that they find in other patients with a high duodenal iron content. They speculate that the zinc-induced metallothionein may be protecting against damaging effects of iron. As a result of the work that has been done on mechanisms of action, including the very important work of these authors, we no longer have to invoke “magic dust” or a “black box” when asserting that zinc blocks copper absorption. We have a very solid mechanism that fits molecular theory (metallothionein has metal regulatory elements in its promotor that bind zinc) as well as clinical research and clinical observations.