Metals in the Environment - Biological Inorganic Chemistry - page 438

enterocytes, regulated by iron regulatory protein (IRP) binding, dietary Cd 2 þ uptake and therefore its toxicity will
depend on the iron status of the individual. Since women have a higher dietary iron intake than men, because of
menstrual blood losses, they are more at risk, and the risk is even greater during pregnancy when DMT1
expression is greatly increased. Cd 2 þ export through the basolateral membrane may not be as efficient as uptake,
since Cd 2 þ accumulates in enterocytes on a high Cd 2 þ diet. The iron transporter at the basolateral membrane,
ferroportin, may also be involved in transport of Cd 2 þ into the blood stream, as may calcium-ATPases and zinc
exporters.
Cd 2 þ enters neurons via voltage-gated calcium channels even in the presence of external calcium, suggesting
that these channels are the main cadmium entry pathway in nerve cells ( Figure 23.2 c ). Since Cd 2 þ is able to cross
even when these channels are blocked, other calcium channels such as ligand-gated N-methyl-D-aspartate
(NMDA) receptors or store-operated calcium channels (Chapter 11) may also participate in cellular cadmium
uptake. Although there is little evidence that cadmium can enter cells via zinc transporters, recent studies suggest
that the zinc transporter ZIP8 is involved in cadmium uptake by mouse testicular cells. Other alternative pathways
for cadmium uptake probably also exist ( Figure 23.2 b ).
Once inside the cell the small, cysteine-rich protein, metallothonein (MT, Figure 23.2 d), which serves to bind
intracellular zinc and copper (Chapter 8), is a major target for cadmium binding. Genes coding for MTare strongly
induced by both Zn 2 þ and Cd 2 þ by activation of the cadmium- (and zinc-) sensitive transcription factor MTF-1.
The importance of MT in cadmium toxicity is underlined by the observation that mice lacking MT are more
sensitive to cadmium exposure than wild-type mice, while MT-overexpressing cells are more resistant. It appears
that the abundant intracellular thiol-containing tripeptide, glutathione, may also be involved in the detoxification
and excretion of cadmium.
The chemical similarities between cadmium and zinc imply that cadmium could probably exchange with this
metal in zinc-binding proteins ( Figure 23.2 e ), although very little concrete evidence has been found in animal
cells, with the exception of metallothionein. Cadmium can alter the intracellular concentration of calcium, which
is an important and universal intracellular signal messenger (Chapter 11). Acute exposure to cadmium can
increase intracellular Ca 2 þ concentration via a poorly characterised cell surface G-protein-coupled “metal-
binding receptor,” GPCR ( Figure 23.2 f), resulting in activation of phospholipase C and IP 3 production by
hydrolysis of phosphatidylinositol. This triggers calcium release from intracellular stores, probably from IP 3 -
gated Ca 2 þ channels in endoplasmic reticulum ( Figure 23.2 g ). This cadmium-dependent upregulation of the
internal concentration of calcium may have consequences for cellular proliferation, differentiation, and apoptosis.
Within the cell, cadmium has the opposite effect ( Figure 23.2 h ). It blocks release of stored Ca 2 þ by inhibiting the
activity of IP 3 and ryanodine receptors (Chapter 11). Cadmium can also increase intracellular calcium concen-
tration in muscle cells by promoting calcium release from the sarcoplasmic reticulum. 5
A considerable number of transcription factors have reactive cysteine residues which enable them to respond to
the redox conditions in the cell. Since cadmium perturbs redox homeostasis, it can affect this class of transcription
factors. If cadmium can displace the tetracoordinate zinc atoms in zinc finger-containing transcription factors, it
will affect them as well. Many of the pathways involving activation and inactivation of transcription factors
involve kinases and phosphatases, themselves under the intricate control of calcium fluxes. It is therefore no
surprise that cadmium will exert effects on the activity of transcription factors, the activation of proto-oncogenes,
and thereby on gene expression ( Figure 23.2 i and i 0 ).
Cadmium also appears to be involved in the ubiquitin proteasome pathway. Ubiquitin binding to proteins is

often signalled by post-transcriptional modifications like phosphorylation ( Figure 23.2 j ). Cadmium has also been
shown to decrease the solubility of specific proteins, and as we saw in Chapter 18, high concentrations of
aggregated proteins can impede the proteasome ( Figure 23.2j ,k). It can also affect protein folding, again with
deficient proteasomal action ( Figure 23.2 l ).

e

5. The sarcoplasmic reticulum is a fine reticular network of membrane-limited elements which pervades the sarcoplasm of muscle cells.