Enzyme key to reaction, scientists say
By Andrew Wineke, Everett Herald, Tuesday, August 4,
1998, p C1 & C2
Why does a single whiff of a chemical make some people
seriously ill, while others don't even notice it?
Researchers at the University of Washington, working with a
team at the University of California at Los Angeles, have begun
to map out how differently people can react to the same
pesticides and chemicals. Some results of their research were
published earlier this month in the science journal Nature.
*
Using common pesticides called organophosphates, such as
diazanon chlorpyrifos and parathion, the scientists have shown
that one person can be 100 times as sensitive to a particular
chemical as another person. The research has also shown that
babies start life with almost no resistance to these pesticides.
"A little bit of difference in metabolism can make a lot
of difference in response," says Clem Furlong, a professor
in the UW's Department of Environmental Health.
The differences stem from an enzyme produced by the body.
Apparently, the same enzyme that is a contributing factor for
vascular disease also regulates resistance to some pesticides.
"Someone with low levels of that enzyme would be very
susceptible to those pesticides," Furlong says.
One outcome of the research is the hope the scientist can
develop an injectable enzyme that would counteract the effects of
the insecticides and nerve agents, such as sarin, which was used
in the Tokyo subway attacks.
There may never be magic bullet to cure chemical sensitivity,
however. No one enzyme or gene can fix all varieties of chemical
sensitivities.
Furlong's research is a long way from explaining chemical
illnesses such as multiple chemical sensitivity or Gulf War
syndrome. The reason is that there are so many chemicals that a
victim might have been exposed to, and, after the fact, there is
no way to measure what doses they could have received.
"If you want to get a really clear cause and
effect," Furlong says, "you need to know how
much."
* [vol. 394, pp. 284-287, July 16, 1998. Abstract below]
Mice lacking serum paraoxonase are susceptible
organophosphate toxicity and atherosclerosis, Diane M. Shih,
Lingjie Gu, Rong Xia, Mohamad Navab, Wan-Fen Li, Susan Hama,
Lawrence W. Castellani, Clement E. Furlong, Lucio G. Costa, Alan
M. Fogelman & Aldons J. Lusis
Serum paraoxonase (PON1) is an eterase that is associated with
high-density lipoproteins (HDLs) the plasma: it is involved in
the detoxification of organophosphate insecticides such as a
parathion and chlorpyrifos String. PON1 may also confer
protection against coronary artery disease by destroying
pro-inflammatory oxidized lips present in oxidized low-density
lipoproteins (LDLs). To study the role of PON1 in vivo, we
created PON1 knockout mice by gene targeting. Compared with their
wild-type literates, PON1-deficient mice were extremely sensitive
to the toxic effects of chlorpyrifos oxon the activated form of
chlorpyrifos, and were more sensitive to chlorpyrifos itself.
HDLs isolated from PON1-deficient mice were unable to prevent LDL
oxidation in a co-cultured cell mode of the artery wall, and both
HDLs and LDLs isolated from PON1-knockout mice were more
susceptible to oxidation by co-cultured cells than the
lipoproteins from wild literates. When fed on a high-fat, high
cholesterol diet, PON1 -null mice were more susceptible to
atherosclerosis than their wild-type literates.
Nature has a Website at http://www.nature.com/
Correspondence and request for materials should be addressed to A.J.L. (e-mail: jlusis@medicine.medsch.ucla.edu ).
Andrew Wineke may be reached at wineke@heraldnet.com
--------------------------------------------------------------------------------------------------------------------------
By LAURIE GARRETT
NEWSDAY
(1996??)
The ability to withstand exposure to the nerve gas sarin is
genetically
controlled, with Caucasians most resistant to the dangerous
chemical and
Asians most susceptible, according to a report released Friday.
The discovery of a genetic basis to sarin vulnerability may have
powerful
implications for investigation of complaints of medical problems
among Persian
Gulf war veterans. Last month, the Department Of Defense admitted
that 20,000
gulf war military personnel may have been exposed to toxic levels
of saran
when an Iraqi stockpile was bombed by U.S. forces. And some may
be suffering
symptoms related to sarin exposure.
"We think that research into possible health effects of
organophosphorus
[sarin type] compounds is important and we welcome responsible
research," said
an official statement released by the Department of Defense on
Thursday.
"We agree that the question of individual genetic
differences may be important
in understanding the susceptibility of certain individuals to
[organophosphorus] exposure. The DOD is currently negotiating a
study that
addresses these concerns."
Chemist Clement Furlong and his University of Washington
colleagues have for
several years studied a class of chemicals called
organophosphates, all of
which exert their lethal effects by blocking a crucial
neurotransmitter called
acetylcholine. Most organophosphates are used as pesticides, but
a few - like
satin - have been developed as nerve gas weapons. The United
States, for
example, has stockpiles - all of which are scheduled for
destruction by 2000 -
of 25,000 tons of such nerve agents.
In the blood of all human beings is an enzyme called Paraxonase,
or PON1,
which normally plays a poorly understood role in cholesterol
metabolism.
Furlong's group demonstrated years ago that PON1 also breaks down
or destroys
the super-lethal component of organophosphates, a chemical called
paraoxon.
Furlong has injected rabbits and other test animals with the PON1
enzyme and
shown that subsequent exposure to usually lethal organophosphate
pesticides is
harmless. In other words, PONI protected -the animals against the
lethal
effects of pesticides by destroying paraoxon.
In Friday's issue of the British publication Nature Genetics,
Furlong's group
shows that PONI has the same effect on sarin, which is not
surprising because
the chemical is a classic organophosphate. But what is startling
is discovery
that some people make a form of PONI that doesn't work against
sarin. The
trait - called type R - is genetic.
People who inherit type R genes from both of their parents,
rendering them
homozygous for the trait, are extremely vulnerable to the toxic
effects of
sarin. People who make normal PON1 - this is regulated by type Q
genes - are
better able to resist the lethal chemical. If one is
heterozygous, having
inherited Q from one parent and R from the other, susceptibility
to sarin is
midway between the two extremes.
A separate, as yet unidentified, gene regulates how much PONI is
made. Even
if a person is homozygous for the beneficial type Q gene, it will
do no good
if the amount of PON1 is low when sarin enters the body.
"Now what I think is real important to do would be to look
at people in Japan
who were exposed to sarin in that [1993 Tokyo subway]
attack," Furlong said,
"to test their PONI enzymes - the genetic forms in those who
got sick vs.
those who didn't."
Gene tests show Asians are most likely to carry the susceptible
type - R
genes. Twenty-five percent of them are homozygous for sarin
susceptibility.
About 16 percent of Latinos are homozygous type R while only 10
percent of
Caucasians are so vulnerable. Researchers have not yet tested
Africans or
African-Americans.
A Department of Defense spokesman said last week that no racial
breakdown of
gulf war veterans who claim war-related illnesses, compared with
the overall
demographics of the 700,000 U.S. troops who served in the war,
has been done.
But the Furlong study suggests two crucial points: People are not
equally
susceptible to the nerve gas, and Pentagon assumptions about
"significant
exposures" - assumptions used in the past to dismiss the
possibility that
chemical weapons were at the root of so-called gulf war syndrome
- may fail to
consider elements of the population that are particularly
genetically
vulnerable to sarin and other nerve gases.
Five soldiers could, for example, have been exposed to the same
sarin dose, at
the same time and only one go on to develop paraoxon-caused
illness.
-----------------------------------------------------------------------------------------------------