Iron - Toxicology of Metals - page 577

in idiopathic hemochromatosis correlate very well
with the extent of iron overload and are effectively
reversed on iron removal. However, it is not estab-
lished whether, in vivo , these lysosomal abnormalities
are an important pathophysiological factor.

of cyclins in various cell lines (Le and Richardson,
2002).

7.2 Evidence That Iron Promotes
Carcinogenesis in Humans Is Lacking
The aforementioned observations are likely respon-
sible for a myth, expressed implicitly or explicitly in
numerous review articles, that iron in excess promotes
carcinogenesis. Two strong arguments against this
idea exist. First, the fact that iron is essential for DNA
synthesis and cell proliferation provides no support
for the conclusion that iron is involved in carcinogen-
esis. Second, clinical evidence that iron in excess plays
a role in pathogenesis of cancers is lacking. The only
iron overloading disease, “classical” HH (see Section
6.2), is the sole condition that can lead to one type
of cancer, hepatocellular carcinoma (Harrison and
Bacon, 2005), which occurs in 19-24% of HH (Kew et
al ., 1990). However, iron overload alone is unlikely to
cause hepatocellular carcinoma, as documented by the
absence of hepatocellular carcinoma in patients with
iron overload caused by repetitive transfusions (Kew
and Popper, 1984). In addition, the presence of cirrho-
sis caused by iron overload seems to be an important
factor in hepatocarcinogenesis. This view is supported
by reports documenting that the risk of hepatocellu-
lar carcinoma persists in cirrhotic patients depleted of
excess iron stores (Fargion et al ., 1992; Niederau et al .,
1985). There is no evidence that patients with HH
would have a higher incidence of extrahepatic tumors
(Bradbear et al ., 1985; Elmberg et al ., 2003).
There are occasional reports that repeated injec-
tions of iron dextran has induced sarcomas in animals,
leading to speculation that at least some sarcomas in
humans could be caused by intramuscular injections of
iron. However, Fielding (1977) analyzed nine human
cases reported in a period of approximately 30 years
(since 1945) and concluded that there was no causal
relationship between sarcomas and iron injections in
humans (see also Chapter 10). Similarly, some reports
claimed that hematite miners and iron foundry work-
ers had a higher incidence of lung cancer mortality
than the rest of the population. However, Stokinger
(1984), who reviewed the world literature, has con-
cluded that no existing evidence supports the notion
that inhaled iron could play a pathogenic role in lung
cancer in humans. (The carcinogenic effects of con-
comitant exposure to agents such as radon and pol-
yaromatic hydrocarbons are discussed in Chapter 10.)
That said, the jury is still out on this question, and we
have recently reported that iron complexed with free
fatty acids (found abundantly in cigarette smoke) read-
ily enters cells. Furthermore, the imported iron leads

7 “CARCINOGENIC” EFFECTS

7.1 Role of Iron in DNA Synthesis
and Cell Proliferation
The requirement for iron in tissue culture medium
has long been known (Bomford et al ., 1986; Hoffbrand
et al ., 1976; Lederman et al ., 1984; Morgan et al ., 1950;
White, 1955), but probably the fi rst convincing experi-
mental evidence demonstrating that iron plays a crucial
role in the initiation and maintenance of DNA synthe-
sis was provided by Robbins and Pederson (1970).
They showed the presence of iron in a nuclear frac-
tion, perhaps associated with a polysaccharide. Even
more importantly, these authors reported signifi cant
inhibition of DNA synthesis in HeLa cells by the iron
chelator desferrioxamine. This has been confi rmed and
elaborated in various cell types, using not only desfer-
rioxamine but also other iron-chelating agents such
as 3,4-dihydroxypyridine (Tsai and Ling, 1971), pico-
linic acid (Fernandez-Pol et al ., 1977), aroylhydrazones
of pyridoxal and salicylaldehyde (Laskey et al ., 1988;
Richardson et al ., 1995), and numerous others (Kon-
toghiorges et al ., 1986). These, and many studies that
followed, have shown that iron limitation arrests cells
in the G1 phase of the cell cycle, but there are reports
indicating that the progression of cells through S phase
and perhaps beyond is iron-dependent (Kühn et al .,
1990; Le and Richardson, 2002).
One plausible link between iron and cell prolifera-
tion is the enzyme ribonucleotide reductase, which
produces the four deoxyribonucleotides from the cor-
responding ribonucleotides (the rate-limiting reaction
in the synthesis of DNA precursors and, therefore,
a key control point in DNA synthesis). In mamma-
lian cells, the enzyme is composed of two noniden-
tical protein subunits: R1, the catalytic subunit that
binds ribonucleotides; and R2, which requires Fe(III)
for the stabilization of a tyrosyl radical. Inhibitors of
ribonucleotide reductase block DNA synthesis and
cell replication; one such inhibitor is the iron chelator
desferrioxamine (Hershko, 1994), which is thought to
act by withholding iron from the nonheme iron sub-
unit of the enzyme. In addition to this “nutritional”
requirement of proliferating cells for iron, this metal
seems to play some kind of “signaling” role in the cell
cycle: iron chelators were shown to decrease levels