Mechanism
of Eukaryotic Arsenic Transport and Resistance
Arsenic,
which usually enters the human system through ordinary drinking water,
can be toxic to cells and is associated with such ailments as cancer,
high blood pressure and diabetes. With
a Life Sciences Corridor grant, Dr. Hiranmoy Bhattacharjee is using a
mouse model to understand how arsenic is detoxified in mammalian
systems. Scientists
know that bacteria can survive high levels of arsenic because they
encode for pumps that transport it out of the cell. The ArsAB pump,
encoded by the ars genes, extrudes arsenic out of the bacterial
cell, thereby reducing the intracellular concentration of the substance
and producing resistance. Dr.
Bhattacharjee has identified a mouse homologue (mARSA) of the
bacterial arsA gene that is 97 percent identical to its human
counterpart. “We don’t
know the exact function of this gene yet, but if its role in humans is
similar to its role in bacteria, we could conclude that animals,
including humans, have an ATP-dependent export pump that mediates
arsenical resistance,” said Dr. Bhattacharjee. This
is particularly important for people in certain areas of Michigan where
elevated arsenic concentrations have been found in the water.
Susceptibility genes combined with high arsenic levels could be
particularly dangerous. Through this study, Dr. Bhattacharjee hopes to
better explain the role of the mARSA protein that may be important in
assessing the risk from arsenic exposure. “Individuals with reduced
ability to extrude arsenic may retain more arsenic and be at higher risk
for toxicity,” he said. “This information could potentially be used
as a genetic marker for arsenic-related diseases.” The
final area of investigation in this study is the role of arsenic in
cancer. It is already known
that human tumor cell lines selected for resistance to arsenic are also
cross resistant to cisplatin (which is used to treat metastatic cancer)
and vice versa. This leads
to the possibility that arsenic resistance pumps may also confer
cisplatin resistance, which could lead to the development of new
chemotherapeutic agents. Collaborating
on this project is Dr. Hyesook Kim, president and director of research
at Detroit R & D, Inc. She will be providing extensive experience in
eukaryotic gene expression. In
addition, Professor Ye-Shih Ho, director of the Transgenic/Knockout
Animal Facility Core in WSU’s Institute of Environmental Health
Sciences, will assist in creating a knockout mouse model to test whether
the mARSA gene is an indication of sensitivity to arsenic. “Arsenic
exposure in the state of Michigan causes both acute and chronic health
problems. The results of this project will be important for determining
the mechanism of arsenic detoxification, thereby allowing improved
treatments for such problems,” said Dr. Bhattacharjee. |
