Understanding copper homeostasis in humans and copper effects on health

Abstract

Concern about human exposure to copperderives from the fact that virtually allindividuals are exposed to it in one way oranother, yet the knowledge about the effectsof chronic excess copper on human healthis clearly insufficient. Cu is an essentialmicronutrient that participates in severalprocesses crucial for life, but at the sametime, it may be toxic to cell membranes,DNA and proteins when accumulated inexcess (1, 6, 10). In man, mechanismsregulate uptake, efflux, storage andutilization of Cu preventing adverse effectsdue to excess within a rather wide range of(dietary) exposure. Cu handling appearstightly regulated, but the upper and lowerlimits of its homeostatic regulation areunclear. When exposure is high enough toinduce clinically apparent manifestations,the available markers are efficient andhelpful for diagnosis. However, thesemarkers are not sensitive enough to revealless intense changes of Cu status, whichmay be relevant in long-term human health(2, 7). Here, we review a series of studies inhumans that we have performed to explorethe capacity to handle copper loads and thelimits of copper homeostasis in humans.In a first, preliminary study, apparentlyhealthy women (20-45y) who had anestimated daily intake of 0.9 mg of copperper day (9, 11) were exposed to a three- tofourfold increase in their basal estimatedcopper exposure. Although acutegastrointestinal symptom report increased,no changes were detected in the distributioncurves of serum copper and ceruloplasminCp (3). In a second study, healthy adultswere exposed to an extra 15 to 150 µg/kg/d,provided via water consumed at home,which was ingested mixed with fluids andfood during the day (2, 3). Although in aproportion of the participants the long-termcopper consumption prior to the study wasestimated borderline low (0.9 mg Cu/day),there was no significant increase inerythrocyte superoxide dismutase (eSOD)activity after the two-month exposureperiod. This result did not support themeasurement of eSOD as a potentialindicator of marginal copper deficiency.Expressed as mean values ± SD, copperconcentrations (in serum, red blood cellsand mononuclear cells), serum/plasma Cp,and eSOD activity were within the normalrange and were not related to copper intake(ANOVA, NS). The non-Cp copper fractionwas positively correlated to serum copper (r= 0.58). Activity of liver aminotransferases,measured as indicators of liver function,remained within normal limits.In the next study, we assessed the effectof the Upper Level (UL) of dietaryrecommendations in apparently healthyadults (4, 5, 8). The UL value is a conceptdeveloped for regulatory purposes to definesafe limits of intake for the normal human. Itis the level of intake from food, water andsupplements that is unlikely to pose risks ofadverse health effects from excess over thelong term, in apparently healthy individuals,in an age- and sex-specific population group(5). Although Cp is not a good indicatorwhen infectious or inflammatory processes