Copper - Toxicology of Metals - page 520

metal to compartments and copper requiring enzymes
by specifi c membrane transporters and cytosolic
molecules named copper chaperones (Arnesano et al .,
2002; Elam et al ., 2002).

5.2 Distribution
5.2.1 Interorgan and Intracellular Distribution

Copper is bound to albumin, transcuprein, and
low-molecular-weight components in the portal
circulation (Hyun and Filippich, 2004; Linder et al .,
1998; Linder and Hazegh-Azam, 1996). The uptake
of copper into the hepatocytes is likely to be medi-
ated by the copper transporter CTR1 (Langner and
Denk, 2004). ATOX1 is involved in the shuttle of cop-
per to ATP7B (Bertinato and L'Abbé, 2004; Langner
and Denk, 2004). ATP7B is localized at the TGN of the
hepatocyte.
Copper is incorporated into ceruloplasmin for
excretion into the blood at physiological copper levels
(Langner and Denk, 2004). The precise mechanism for
copper insertion into ceruloplasmin is unknown (Bielli
and Calabrese, 2002).
At high copper levels, the intracellular traffi cking is
targeted to a post-Golgi vesicular compartment for bil-
iary excretion (Langner and Denk, 2004). Excess copper
in the hepatocyte is bound to metallothioneins (Wij-
menga and Klomp, 2004). Humans with the genetic disor-
der aceruloplasminemia do not have severe disturbances
in the copper homeostasis, suggesting that ceruloplas-
min is not of fundamental importance for appropriate
targeting of copper to the peripheral tissues (Gitlin,
1998).
Also extrahepatically, the intracellular uptake of
copper may be mediated by the high-affi nity CTR1
and the low-affi nity CTR2, which are differently
expressed in human cells (Bertinato and L'Abbé,
2004). High levels of CTR1 are expressed in the
liver, heart, and pancreas; intermediate levels in the
intestine; and low levels in brain and muscle (Berti-
nato and L'Abbé, 2004; Pena et al ., 1999). The highest
expression of CTR2 is in the placenta, with very low
abundance in liver and intestine (Bertinato and L'Abbé,
2004; Pena et al ., 1999). Once inside a cell, copper is
coupled to chaperones for appropriate intracellular
targeting. For instance, copper is shuttled by CCS (Cu
chaperone for superoxide dismutase 1) for copper
incorporation into the Cu-Zn-dependent superoxide
dismutase. Many copper chaperones are known
(Prohaska and Gybina, 2004), and some are described
later. The total body copper of a healthy 70-kg man
has been estimated at 110 mg. The skeleton, muscles,
liver, and brain contain the highest total amounts of
copper (Linder et al ., 1998).

5.1 Absorption

5.1.1 Inhalation

There are no quantitative data from animal or
human studies on the extent of absorption of copper
compounds after inhalation. A pulmonary half-time of
7.5 hours was reported after intratracheal instillation
of CuSO 4 to male Wistar rats (Hirano et al ., 1990).
Intratracheal instillation of particles in the respirable
range containing CuO to male Wistar rats resulted
in a pulmonary half-time of 37 hours (Hirano et al .,
1993). This suggests a faster pulmonary clearance of
more soluble copper compounds compared with less
soluble copper compounds. In both studies, an induc-
tion of the metallothionein synthesis in the lungs was
observed.

5.1.2 Ingestion

Dietary copper is absorbed across the mucosal mem-
brane in the small intestines, but also to a limited extent
in the stomach in mammals (Pena et al ., 1999). Gas-
trointestinal absorption of copper in adults apparently
depends on the amount of copper in the diet, from 55.6%
at 0.78 mg/day to 36.3% at 1.68 mg/day and 12.4% at
7.53 mg/day (Turnlund et al ., 1989). Even higher absorp-
tion, ranging from 62-79%, has been reported. Women
absorbed slightly more copper than men in that study
(Johnson et al ., 1992). There is some evidence that active
transport mechanisms are involved at lower dietary lev-
els, whereas passive diffusion may occur at higher levels
(Varada et al ., 1993). The roles of the highly copper-specifi c
protein Cu transporter 1 (CTR1), as well as the divalent
metal transporter 1 (DMT1), in the gastrointestinal
absorption from the intestinal lumen across the apical
membrane into enterocytes is currently not completely
explained (Harris, 2001; Pena et al ., 1999). Both proteins
are expressed in abundance in the intestines (Tapiero
et al ., 2003). Copper seems to modify the expression of
DMT1 (Sharp, 2003).
Most absorbed copper is retained within the mucosal
cells, bound mainly to metallothionein or glutathione
(Tapiero et al ., 2003). After uptake into the enterocyte,
copper is shuttled to the trans-Golgi network (TGN)
by the chaperone ATOX1 (antioxidant protein 1) (Berti-
nato and L'Abbé, 2004; Tapiero et al ., 2003). The copper
effl ux into the portal circulation is probably mediated
by ATP7A (Menkes protein) (Pena et al ., 1999; Tapiero
et al ., 2003).

5.2.2 Molecular Genetics of Intracellular Transport

Because of its highly reactive nature, copper would
be harmful if present as free ion in cells. Both Cu(I)