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Scientists Find Key to Copper Absorption, Essential to Life

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Duke Health News 919-660-1306

DURHAM, N.C. -- Humans, animals and plants require copper to
live, and scientists have now discovered how cells absorb this
mineral that fuels the brain, heart and other vital organs.

Knowing how copper enters cells could prove essential to
treating copper deficiencies in humans, said the scientists
from Duke University Medical Center who made the discovery.
People derive copper exclusively from their diet. The mineral
is found abundantly in shellfish, legumes, red wine, nuts,
seeds and chocolate, among other sources.

Although too much copper is toxic, copper deficiencies in
adults can trigger brain deficits, heart enlargement, visual
impairment, anemia (low iron), skin and hair breakdown, and
other organ damage.

Babies born without the ability to absorb and transport
copper -- a disorder called Menkes disease -- die in childhood.
But injecting the mineral into children with Menkes has not
proven beneficial, because cells may lack the ability to
utilize it properly, according to the Duke researchers.

Giving copper supplements to adults has proven more
effective in alleviating their symptoms, but scientists have
been unclear as to what controls copper absorption in the first
place.

The Duke team studied copper absorption in mice and
identified, for the first time, the cellular gateway through
which copper passes. An identical gateway is present in humans,
as well as in other animals and plants, the researchers said.
The gateway is a copper "transporter," a specific pore on the
surface of intestinal cells that funnels copper inside the
intestinal walls. From there, copper is absorbed by the
bloodstream and distributed throughout the body to serve as an
engine to jump-start the activity of dozens of proteins that
carry out essential functions.

The researchers published their findings in the September
2006 issue of the journal Cell Metabolism, now available
online. The study was funded by the National Institutes of
Health and the International Copper Association.

"Identifying this transporter could enable the medical
community to develop more effective ways of delivering copper
to deficient children and adults," said study leader Dennis J.
Thiele, Ph.D., professor of pharmacology and cancer biology.
"Without copper, many biochemical processes either do not
happen or happen at a reduced level, which results in a wide
range of health impairments."

Among its roles, Thiele said, cells use copper to help
destroy molecules called free radicals that contribute to aging
and cancer; blood requires copper to clot properly; skin
requires copper to form collagen and melanin; cells cannot
absorb iron without copper; and embryos cannot grow and develop
without copper. Copper imbalances have even been implicated in
Alzheimer's disease, although the evidence is preliminary,
according to Thiele.

In searching for the mechanism for copper absorption in
cells, the researchers focused on a protein called Ctr1, a
binding site or "receptor" that sits on the surface of cells in
the intestine. Thiele's group, which is also affiliated with
the Sarah W. Stedman Nutrition and Metabolism Center at Duke,
had previously implicated Ctr1 as important in copper
metabolism.

To further investigate its role, the researchers genetically
manipulated pregnant mice so their developing fetuses lacked
the gene that controls production of Ctr1 in the intestines.
When the offspring were born, they could not absorb copper and
dispatch it via the bloodstream throughout the body, the
scientists found.

As a result, the pups weighed half the size of their normal
counterparts, had striking defects in the enzymes that generate
energy, had pale skin color, and had deformed whiskers that
were kinky and brittle. Within three weeks the pups had died,
said Thiele.

The researchers took a second set of copper-deficient
offspring and injected them with copper, within five days of
birth, to determine if copper could rescue them from death. The
mice are still alive after seven months -- normal mice live for
two years -- and they are displaying fewer health problems
associated with copper deficiency.

The researchers speculate that delivering copper shortly
after birth, during critical windows of development, could
stave off potential health problems due to copper deficiency.
The infusion of copper would enable essential biochemical
reactions to occur as organ systems are developing and forming.
Once organ systems are fully developed, they are less
susceptible to low levels of copper, the researchers
speculate.

"Before birth and the weeks and months thereafter are
crucial times when the body requires copper to build muscles,
organs, brain connections and many other physiologic
functions," Thiele said.

While rare in children, copper deficiencies are likely to be
more common among adults than generally realized, Thiele said.
People in the general population may have variations of the
gene for Ctr1, called polymorphisms, which can reduce their
ability to absorb and use copper without blocking it
completely.

The current study will serve as a model for understanding
what causes genetic errors in copper absorption and metabolism,
Thiele said. His team will continue to study how the Ctr1
transporter functions and what errors in gene coding might
contribute to health problems such as abnormal heart and brain
function.

Thiele said that studying Ctr1 will help clarify how this
copper transporter evolved in living organisms. Ctr1 has been
preserved in its structure and function throughout all
organisms, from yeast cells to human cells. This means the
transporter evolved very early on, before organisms began to
diverge in their genetic diversity, emphasizing the importance
of this copper delivery mechanism.

Other researchers who participated in the study were
Yasuhiro Nose and Byung-Eun Kim.

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