the 19 50s, this disorder affected m any residents o f Japan’s
Jinzu R iver basin w ho consum ed rice that had been irri-
gated w ith water contam inated from an upstream m ine.
D aily ingestion o f cadm ium w as in excess o f 300 /xg, ap-
proxim ately six tim es the average intake in the U nited
States and in parts o f Europe. M any victim s w ere m ulti-
parous w om en 4 0 -7 0 years o f age, a group at risk for o steo-
m alacia. Their diet w as deficient in calcium and vitam in D.
L ess severe exam ples o f cadm ium poisoning are known.
Cadm ium also disrupts the m etabolism o f iron, copper, and
zinc in hum ans and in several sp ecies o f farm anim als.
M ajor sources o f lead include fum es from com bustion o f
leaded gasoline, flakes o f lead-based paint, and alcoholic
beverages brewed or distilled in lead-containing vessels.
T he first tw o sources have been im plicated in lead poison-
ing o f children from inner-city areas. Children are more
susceptible to lead poisoning than adults; adults absorb
about 10% o f an oral dose o f lead, w hile children 3 -5 years
o f age absorb about 40% o f the sam e dose. L actose en-
hances intestinal absorption o f lead (and calcium ). Uptake
o f im m unoglobulins from maternal m ilk in the intestines
o f very young children occurs by pinocytosis, w hich could
provide a route for lead uptake. Lead inhibits renal
hydroxylation o f vitam in D m etabolites, w hich may con -
tribute to the hypocalcem ia seen in children with high
plasm a concentration o f lead (> 60 /xg/dL). Lead inhibits
hem e biosynthesis (Chapter 29). Severe lead poisoning
can cause lead encephalopathy.
A lum inum accum ulates in the bones o f patients undergo-
ing long-term hem odialysis. It is strongly im plicated as
the cause o f d ialysis encephalopathy (“dialysis dem en-
tia”), and it produces an osteodystrophy that responds
poorly to vitam in D. U se o f deionized water to pre-
pare the dialysates has largely eradicated these problem s.
D eferoxam ine, used to treat hem ochrom atosis (Chap-
ter 29), increases alum inum excretion in these patients
by form ing a w ater-soluble com plex with alum inum that
can be rem oved by dialysis. Chronic use o f alum inum -
containing antacids to reduce intestinal phosphate absorp-
tion in urem ic patients contributes to alum inum overload.
A n increase in serum alum inum concentration and in bone
alum inum content, accom panied by severe osteom alacia,
occurs in infants with azotem ia w ho are given large doses
o f alum inum hydroxide to reduce phosphate absorption.
Intestinal absorption o f alum inum seem s to be increased
in hyperparathyroidism . The m etal inhibits hexokinase,
A LA -dehydratase, and isocitrate dehydrogenase and de-
creases N a+ , K + -ATPase activity, M g2+-ATPase activ-
ity, and choline uptake into synaptosom es.
m inum displaces m agnesium from M g2+-ATP com plexes,
and it could thus antagonize virtually any phosphate-
transferring reaction that uses M g2+-nucleotide triphos-
phate com plexes.
Other Trace Elements
Chronic exposure to silver produces a bluish skin d iscol-
oration know n as
G old poisoning has resulted
from the use o f gold salts for treatment o f arthritis. P oison -
ing from antim ony, arsenic, bism uth, mercury, and thal-
lium is w ell known.
are sm all proteins (M .W . ~ 7 0 0 0 ),
rich in sulfhydryl groups, that bind cadm ium , zinc, and
sm all am ounts o f copper, iron, mercury, and perhaps other
heavy m etals. W ithin a species, m ultiple m etallothioneins
occur that differ in am ino acid com position. T hese pro-
teins typically contain 20 cysteine residues but no disul-
fide bonds and no arom atic am ino acids. They bind one
atom o f cadm ium or zinc for each three sulfhydryl groups.
B inding o f copper to m etallothionein is som ew hat differ-
ent, since a greater number o f m etal atom s are bound per
protein m olecule. M etallothioneins occur particularly in
liver and kidney but also in the intestine and other tis-
sues. Synthesis o f the m etallothioneins is increased by
the m etals that they bind, by dexam ethasone, and by
m any other agents. Cadm ium and zinc are potent induc-
ers in the intestine and in cultured H eLa cells, w hile
copper induces intestinal m etallothionein only weakly.
The m etals and dexam ethasone act by increasing tran-
scription o f m etallothionein gen es. M etal binding also in-
creases the stability o f the apoproteins; m etals also cause
greater accum ulation o f m etallothionein than dexam etha-
The p hysiological role o f m etallothioneins rem ains un-
known, but it m ay be, in part, to protect cells from m etal
toxicity by binding metal ions. M etallothioneins may also
be important for intestinal and renal absorption o f m etals
and for m etal storage and excretion.
37.5 Essential Trace Elements
Table 37-4 sum m arizes current know ledge o f the essential
trace elem ents. B rom ine, cadm ium , lead, and tin m ay also