|
It is now very clear that an individual's genetically determined complement
of detoxication enzymes has a significant influence on their response
to a variety of therapeutic drugs and environmentally derived toxins
The work of the Molecular Genetics Group is aimed at gaining a fundamental
understanding of the molecular and biochemical mechanisms that underlie
individual responses to such compounds. One of the major research interests
of the Molecular Genetics Group is the role played by the glutathione-linked
enzymes such as the glutathione transferases (GSTs) in the metabolism
and detoxification of therapeutic drugs and environmentally derived
carcinogens and toxins.
The GSTs are a large family of enzymes and previous studies have shown
that they can be subdivided into a number of different classes that
have characteristic structural variations, substrate preferences and
sites of expression. The GSTs function by conjugating glutathione to
the target chemical thereby making it more water soluble and making
it recognisable by an export pump that expels glutathione conjugates
from cells.
Genetically determined deficiency in the expression of some GSTs can
be a risk factor for lung, stomach and skin cancer. In contrast, over
expression of GSTs has been associated with resistance to cancer chemotherapy.
Genetic variations that cause subtle changes in GST function can be
clinically important. For example, we found that a variant form of glutathione
transferase GSTP1 that works with different substrates was associated
with the occurrence of Parkinson's disease in patients who had been
exposed to pesticides.
To gain a comprehensive understanding of the genetic diversity in
response to environmental toxins and therapeutic drugs it will be necessary
to identify all the enzymes involved in detoxication processes and to
identify the common genetic variants of these enzymes that contribute
to functional differences. The recent expansion of the Expressed Sequence
Tag database (EST) to include more than a million DNA sequences encoding
copies of most active human genes has provided a remarkable resource
for the identification of new genes and polymorphisms. We have developed
novel screening strategies that have successfully identified several
new glutathione transferase gene families and a number of novel polymorphisms.
The new enzymes discovered by this data mining approach have been
shown to catalyse unique detoxification reactions and to participate
in metabolic pathways not previously attributed to the action of glutathione
transferases. For example we recently discovered that a GST we have
termed Omega can inhibit ryanodine receptor calcium release channels
in the heart. This enzyme also plays a role in the metabolism of arsenic.
Another GST we have discovered and called Zeta is involved in the metabolism
of compounds such as dichloracetic acid (DCA) which is known to cause
cancer in mice. Significantly, DCA is a contaminant of chlorinated drinking
water
The strategies we have developed for screening the EST database can
be readily applied to other genes and gene families and will be of great
value in the identification of new genes and polymorphic variants of
pharmacogenetic interest.
|
