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.
