The journey to find genes responsible for determining sensitivity
or resistance to specific insecticides led to the paraoxonase
(PON1) gene on human chromosome 7. This gene encodes a 355 amino
acid protein that is localized on the high density lipoprotein
(HDL) particles in plasma. Characterization of this gene revealed
that different individuals expressed both different forms of this
enzyme with amino acid substitutions at positions 55 and 192 as
well as different levels of this protein. Additional studies showed
that mutations in the regulatory region of the PON1 gene
contributed to the very different levels of plasma PON1 among
individuals. It turned out that both the level of the enzyme as
well as the amino acid present at position 192 (glutamine or
arginine) are important in determining resistance to the active
forms of specific organophosphorus insecticides, especially
diazinon and chlorpyrifos. The position 192 amino acid also
determined whether an individual's plasma hydrolyzed the nerve
agents soman and sarin at high or low rates. It is not yet known
whether these different rates of hydrolysis observed in biochemical
assays reflect differences in sensitivity of individuals to nerve
agents. Taken together, all of the experiments carried out to date
indicate that engineered recombinant PON1 is an excellent candidate
to use for treating cases of poisoning by specific organophosphorus
compounds. The available data on the relationship of PON1 levels
and position 192 genotype led us to introduce the term PON1 status
to describe an individual's PON1 plasma level as well as their
position 192 genotype.
The characterization of the genetic variations of the PON1 gene
together withexperiments showing that HDL can protect the lipids in
low density lipoprotein particles (LDL) from oxidation and that it
was PON1 that was responsible for this protection have opened an
entirely new area of investigation, the role of PON1 in protecting
against vascular disease.
More recent reports have noted that PON1 also metabolizes a
number of drugs, activating some and inactivating others.
This book describes the recent advances in understanding the
role of PON1 in both cardiovascular disease and toxicology of
insecticide exposure as well as some of the recent information
indicating an important possible role in the pharmacokinetics of
drug metabolism. The final chapter of the book provides an overview
of the areas of PON1 research and suggests future directions for
research on PON1 as well as the related, linked genes PON2 and
PON3.
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