Essential Trace Elements
be essential, but the evidence is not convincing. Many
of these elements are toxic when present in excess, and
cause changes in membrane permeability or inhibition of
vital enzyme processes such as protein synthesis, oxidative
phosphorylation, and DNA replication. Chronic exposure
to these elements may cause other, poorly understood, dis-
orders. Copper and zinc are discussed below because they
have been most thoroughly studied and their involvement
in human disease is well documented. Iron and iodine are
discussed in Chapters 29 and 33, respectively; cobalt is
discussed in Chapter 38.
Copper is necessary, together with iron, for hematopoiesis,
probably partly because it is needed for the synthesis of fer-
roxidase (ceruloplasmin). Many enzymes require copper
for activity. Examples of some of the copper-enzymes and
their functions are given in Table 37-5. Mitochondrial iron
uptake may be blocked by deficiency of a cuproprotein,
perhaps cytochrome oxidase. Several inherited diseases
involving abnormalities in copper metabolism (Wilson’s
disease, Menkes’ syndrome) or copper enzymes (X-linked
cutis laxa, albinism) occur in human and in several animal
The oxidation state of copper in biological systems is
+1 or +2. Copper(III) is found in inorganic systems and
may occur as a reaction intermediate in galactose oxidase,
laccase (a plant enzyme), and perhaps other enzymes. The
coordination number of copper in these enzymes ranges
from two to six and occasionally higher.
The average adult human contains 70-100 mg of copper.
The highest concentrations (in decreasing order) are in
liver, brain, heart, and kidney. Muscle contains about 50%
of total body copper. Of the remainder, about one-fifth is
in the liver (3-11
Human erythrocytes contain 1.0-1.4
of copper per
milliliter, of which more than 60% is in superoxide dismu-
tase. Normal serum contains of copper and 20CM-00 mg/L
of ceruloplasmin. Whether copper is released from cerulo-
plasmin by endocytosis or by conformational change fol-
lowing binding of ceruloplasmin to a membrane receptor
Copper is absorbed from food in the upper small intes-
tine. The absorption is primarily dependent on the quantity
of the copper present in the diet. High intake of zinc di-
minishes copper absorption by inducing metallothionein
formation in the mucosal cells. Metallothioneins, due to
their high affinity for copper, bind it preferentially and the
bound copper is lost during the sloughing of cells from
the villi. Copper accumulation in patients with
can be reduced by giving oral zinc acetate, which
decreases absorption (discussed later). Absorbed copper is
transported to the portal blood where it is bound to albu-
min (and probably transcuprein), amino acids, and small
peptides. Copper binds to albumin at the N-terminal tripep-
tide (Asp-Ala-His) site. The recently absorbed copper is
taken up by the liver, which plays a central role in copper
Copper occurs in many foods; particularly good sources
are liver, kidney, shellfish, nuts, raisins, and dried legumes.
Copper deficiency due to diet is rare except in malnutri-
tion and in children with chronic diarrhea. It occurs in
total parenteral nutrition with fluids low in copper, partic-
ularly following intestinal resection and in patients who
receive large amounts of zinc to improve wound healing
or for management of sickle cell anemia. Copper is often
removed from prepared foods to increase their shelf life.
TA B LE 37-5
Examples o f Copper-Containing Enzymes and Their Functions
1. Cytochrome c oxidase
2. Superoxide dismutase
5. Dopamine ß-monooxygenäse
. Lysyl oxidase (also called protein-lysine
7. Peptidylglycine mono-oxygenase
. Amine oxidases
Terminal enzyme of mitrochondrial electron transport;
Inactivation of reactive oxygen species; antioxidant defense.
Ferroxidase; Iron metabolism.
Synthesis of melanin.
Synthesis of norepinephrine and epinephrine.
Required for cross-linking of collagen and elastin; maturation
Required for removal for carboxy terminal residue and
a-amidation; Processing and maturation of neuroendocrine
and gastro-intestinal peptide hormones.
Deamination of primary amines.