Chemistry Reference
In-Depth Information
CHAPTER
5
Selected Molecular Mechanisms of
Metal Toxicity and Carcinogenicity
TODD DAVIDSON, QINGDONG KE, AND MAX COSTA
1 TRANSPORT OF TOXIC METALS BY
MOLECULAR/IONIC MIMICRY
OF ESSENTIAL COMPOUNDS
ABSTRACT
This chapter will summarize some of the molecular
responses exhibited by cells that come into contact
with toxic metals. We will consider the transport of
toxic metals into cells and how this interferes with the
transport of essential metals. Toxic metals also inter-
fere with the intracellular action of essential metals
and may cause toxicity and cancer by this mecha-
nism. Some metals have very specialized effects on
enzymes, and there are proteins that can bind toxic
metals such as metallothionein, which will also be
discussed. Some metals are also slightly mutagenic
and genotoxic, and these effects will be discussed.
Because most metals that are carcinogenic, such as
nickel (Ni), arsenic (As), beryllium (Be), and cad-
mium (Cd), with the exception of chromium (Cr),
do not interact with DNA and are not mutagenic, we
discuss other mechanisms such as epigenetic effects
to account for their carcinogenic activity, as well as
how they affect the expression of genes. Metals also
interfere with cell signaling, and, in particular, we
will discuss the hypoxic signaling pathway as well
as those involving PI3K, AKT, ROS, MAPK, NF
1.1 Introduction
Metals are found throughout the environment, and
although certain metals are highly toxic, others are
essential to living systems. Essential metals are needed
in the diet to maintain proper human health, because
they cannot be synthesized by the body and are required
for enzyme reactions or other physiological processes.
The cellular uptake and export of these essential met-
als is tightly regulated by various homeostatic trans-
port mechanisms, because an excess of, or lack of, an
essential metal, can also be toxic. Some of these proc-
esses are very specifi c, whereas others are more promis-
cuous and are able to transport a multitude of metals
that are potentially toxic. Transport proteins may recog-
nize nonessential metals because they resemble essen-
tial metals or other compounds, effectively acting as
molecular mimics. Unregulated transport of nonessen-
tial metals or deregulation of essential metal transport
is a major factor in determining the potential toxicity or
carcinogenicity of metallic compounds. In fact, various
diseases are caused by alterations in metal transport
and metabolism. The transport of a number of metals is
discussed here, but more detailed reviews are available
(Ballatori, 2002; Clarkson, 1993; Goyer, 1997).
B,
NFAT, and AP1. Finally, the basis of the interaction
of toxic metals with all cellular constituents involves
their coordination with biological ligands, which will
be addressed throughout the chapter.
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