section 37.5
Essential Trace Elements
897
that prevents their interference with penicillamine. Tri-
ethylenetetramine, another copper-chelating agent, may
be of particular value in patients who are or who are be-
coming sensitive to penicillamine. As discussed earlier,
since excessive zinc prevents copper absorption, oral in-
take of zinc acetate is used in the management of Wilson’s
disease.
Menkes’ syndrome (Menkes’ steely-hair syndrome) is
a rare, X-linked recessive disorder in which infants have
low levels of copper in serum and in most tissues ex-
cept kidney and intestine, where the concentration is very
high. They also have greatly reduced plasma ceruloplas-
min levels. Hair of the affected infants has a characteris-
tic color and texture
(pili torti,
“twisted hair”). It appears
tangled and dull, has an ivory or grayish color, and is fri-
able. Weakness and depigmentation of hair and defects
in arterial walls (leading to aneurysms) are explained by
loss of activity of copper-dependent enzymes (Table 37-5).
Cerebral dysfunction may be due to a disturbance in en-
ergy metabolism or neurotransmitter synthesis secondary
to decreased activity of cytochrome oxidase and dopamine
ft
-hydroxylase.
The defect in copper metabolism is generalized, and
the degenerative changes cannot be reversed by parenteral
copper administration. However, parenteral copper admin-
istration corrects the serum ceruloplasmin and hepatic cop-
per deficiencies. Other tissues take up copper administered
parenterally, but activities of their copper enzymes are not
normalized. The failure of postnatal treatment is due to the
fact that many of the deleterious effects occur
in utero.
The molecular defect in
Menke’s syndrome,
like that
in Wilson’s disease, resides in a P-type ATPase. The gene
for the enzyme is located on the X chromosome. Wilson’s
disease is characterized by defective biliary excretion; in
Menkes’ syndrome, the defect is a failure to transport cop-
per to the fetus during development as well as failure to
absorb copper from the gastrointestinal tract after birth.
Aceruloplasminemia
is an autosomal recessive disor-
der characterized by progressive neurodegeneration and
accumulation of iron in the affected parenchymal tissues.
Iron accumulation in this disorder is consistent with ceru-
loplasmin’s role as a ferroxidase in iron metabolism (dis-
cussed in Chapter 29).
Zinc
Zinc is a necessary nutrient in animals. The discovery that
zinc deficiency is the cause of parakeratosis in pigs was the
first demonstration of the practical importance of zinc in
animal nutrition. More than 100 zinc enzymes are known,
many of which are in the liver and include examples from
all six classes of enzymes. In these enzymes, zinc may
have a regulatory role or be required for structure or for
catalytic activity. Zinc is not readily oxidized or reduced
from its usual oxidation state of
+ 2
and is not involved in
redox reactions.
Table 37-6 lists some zinc-containing enzymes im-
portant for mammalian metabolism. Zinc has an impor-
tant regulatory function in fructose-
1
,
6
-bisphosphatase
and has structural catalytic and regulatory roles in DNA
and RNA polymerases. Many of the transcription factors,
namely, DNA-binding proteins, contain zinc finger motifs
consisting of Zn2+ bound to four cysteine or two cysteine
and two histidine residues in a coordinate covalent link-
age (Chapter 26). Thymidine kinase is also a zinc enzyme.
Zinc is present in gustin, a salivary protein secreted by the
parotid glands that may be necessary for proper develop-
ment of taste buds. A common sign of zinc deficiency is
hypogeusesthesia. Gustin is structurally similar to nerve
growth factor (NGF) isolated from male mouse submax-
illary glands and other sources, which contains
1
mol of
zinc per mole of protein. The metal prevents autocatalytic
activation of NGF. Along with copper, zinc is required for
activity of superoxide dismutase (Table 37-5).
In pregnant rats, zinc deficiency adversely affects fetal
development and parturition and produces fetal abnormal-
ities perhaps because of a requirement of zinc for gene
expression. It is involved in synthesis, storage, and se-
cretion of insulin by pancreatic islet
ft
cells. Physiolog-
ical stresses, such as trauma, infections, and low protein
intake, cause a decrease in the plasma zinc level. Zinc
can substitute for iron in protoporphyrin IX during heme
synthesis, and quantitation of zinc protoporphyrin in ery-
throcytes is useful for evaluating iron deficiency anemia.
Zinc interacts with plasma membranes of many cells, in-
cluding erythrocytes (see below), and it may be vital for
their structural integrity. The metal also has roles in wound
healing, male fertility, bone formation, and cell-mediated
immunity.
A healthy 70-kg man contains 1.4-2.3 g (~30 mmol)
of zinc. The prostate gland is rich in zinc (about 100 /ig
Zn2+ per gram wet weight), as are prostatic secretions and
semen. In rats, prostatic zinc concentration is decreased
by castration and increased by administration of testos-
terone or gonadotropin. Testicular atrophy and failure of
spermatogenesis occur in zinc-deficient rats. The skin con-
tains approximately 20% of total body zinc. Dermatitis and
poor wound healing are the most common symptoms of
zinc deficiency in patients receiving total parenteral nu-
trition with zinc-deficient fluids. Zinc supplements do not
promote wound healing when zinc stores are adequate.
Bone has a high zinc content (>100 /ig/g); however, bone
zinc is not readily mobilized. Hair and nails also have high
concentrations of the metal.
