conspectus of researchon copper metabolism and requirements

1986 KARL E. MASON
min also has the capacity to oxidize natu
rally occurring substances such as sero
tonin, melatonin, epinephrine and norepinephrine,
and may possibly play an
important role in the control of blood and
tissue levels of biogenic amines (585).
There are also suggestions that abnormali
ties in copper metabolism may be involved
in Parkinson's disease (34). For further
details concerning the multifunctional na
ture of ceruloplasmin, its biological func
tions and catalytic activity the reader is
referred to the recent reviews of Frieden
and Hsieh (230) and of Sass-Kortsak and
Beam (668).
Ceruloplasmin is not the only compound
with ferroxidase-like activity in human
plasma. In 1969, Lee et al. (444) reported
the presence of citrate, differing from
ceruloplasmin in that it is not inhibited by
azide and yet has the same capacity to
accelerate oxidation of ferrous ion to ferric
ion and, possibly, to accelerate the rate of
reaction of ferric ion with transferrin. Ad
ditional mechanisms, perhaps not involving
copper directly, have been implicated in
iron translocation (56a). A deterrent to
recognition of a role of ceruloplasmin in
hematopoietic functions of man has been
the finding that many subjects suffering
from Wilson's disease may have no demon
strable plasma ceruloplasmin and yet show
no evidence of iron-deficiency anemia.
This anomaly seems now to have a reason
able explanation with the isolation of an
other cuproprotein from human serum by
Topham and Frieden (788) which nor
mally accounts for about 1% of the total
ferroxidase activity. It has a molecular
weight of about 800,000 daltpns and con
tains approximately 0.8% copper. Its desig
nation as ferroxidase II seems quite appro
priate. It is a lipoprotein with a cholesterol
and phosphatidylcholine content of ap
proximately 207o- It differs from cerulo
plasmin also in its yellow color and its lack
of p-phenylenediamine oxidase activity,
and may be responsible for the mainte
nance of near-normal iron metabolism,
despite low-levels or absence of plasma
ceruloplasmin, in Wilson's disease. Whether
citrate plays a comparable role is still a
question. Furthermore, most of the new
postulations with respect to the roles of the
ferroxidases and citrate are based upon in
vitro studies on human blood and observa
tions on experimental animals. Their appli
cability to man seems reasonable but re
mains to be established.
Other intriguing aspects of ceruloplas
min are: 1) its increased plasma levels in
response to estrogenic hormones, as in
users of oral contraceptives and pregnant
women; 2) its very low levels in plasma
of the fetus and newborn; 3) its rapid
synthesis by the newborn infant through
utilization of a special neonatal hepatomitochondrocuprein
not found at any other
stage of life; 4) its stabilization at adult
plasma levels at or about puberty; 5) its
low serum levels in the genetically deter
mined Wilson's and Menkes' diseases;
and 6) suggestions that copper is incor
porated into cytochrome c oxidase only if
it is presented to the cell as ceruloplasmin
(3, 65). These topics will be considered
later.
Superoxide dismutase
Almost 40 years ago, Mann and Keilin
(486) isolated two blue copper proteins
from bovine erythrocytes and liver which
they designated hemocuprein and hepatocuprein,
respectively. Both proteins had
molecular weights of about 35,000 daltons
and contained 0.34% copper. Similar pro
teins were later isolated from human eryth
rocytes (erythrocuprein) by Markowitz et
al. (490), from human brain (cerebrocuprein)
by Porter and Ainsworth (612)
and from adult human liver (hepatocuprein)
by Porter et al. (616).
Subsequently, Carneo and Deutsch (95)
clearly demonstrated that these copper
proteins were identical and proposed the
term cytocuprein to encompass them. They
later considered the term inappropriate,
since the protein also contained 2-g atoms
of zinc per mole (96). On the basis that
these cuproproteins catalyze the dismutation
of superoxide-free radical ions, and
thus have true enzymatic function, the
designation "superoxide dismutase" was
proposed by McCord and Fridovich (500,
501), and is now in common usage. The
primary function of superoxide dismutase
appears to be that of scavenging the inter
mediates of oxygen reduction in aerobic
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