Agatha Christie's favorite murder weapon was rat poison _specifically, arsenic trioxide. It was readily available as "ratsbane"during the 1930s, when she wrote _ and subtly effective.

Nowadays we have other poisons, far more effective, notably thenerve gases sarin and soman. Their fatal dose in humans is 0.01milligrams per kilogram. That is, it takes only 70 or so milligrams todo in a 170-pound man. These lethal agents work by blowing thefuses on cholinesterase, an enzyme in the body that breaks down animportant neurotransmitter, and largely controls the nervous system.They kill people by stopping their breathing.

Under the anti-chemical-warfare treaty, the U.S. has pledged todestroy some 25,000 tons of chemical agents by the end of thisdecade.

Sarin surfaced in the news in March 1995, when Japanese cultistsreleased it in the Tokyo subway system, killing several people andincapacitating many more. Now it's back in the headlines, because ofsuspicion that destruction of Iraqi sarin weaponry during the GulfWar sickened U.S. troops.

But similar cholinesterase blockers incapacitate three million peoplea year worldwide, killing 220,000 of them. These are not militaryanti-personnel arms but agricultural pesticides and herbicides.Mostly, they expose farm workers who spread and spray insecticidescontaining the same chemical ingredients, namely, organophosphorus(OP) compounds.

Which is why your household aerosol can of roach, rodent or weedkiller carries a warning label: "hazardous to humans and domesticanimals."

The widest used of industrial crop-protecting cholinesteraseinhibitors until recently was parathion, a chemical first cousin of sarinand soman. Ingestion, inhalation, even skin contact can producefatalities. In a recent year, U.S. manufacture of parathion topped 2.7million pounds.

Happily, there's a natural enzyme in the human body that detoxicatesOPs, including parathion. This enzyme, paraoxonase (PON1 forshort), is present in human blood serum. It inactivates a number oforganophosphates, among them sarin and soman, by hydrolyzingtheir phosphorus-fluorine bonds.

Unhappily, the gene that makes this self-defense enzyme has mutantvariants, which determine the level of resistance in an individual.

PON1 works best against low, chronic exposure to the poison; lesswell against a high, acute dose. Interestingly, this enzyme isphysically attached to the high-density lipoprotein (HDL), known asthe "good-guy" molecule against cholesterol build-up in the body.

Enzyme Reverses Field On Detoxication

Now, new research finds that a person's susceptibility to OPpoisoning depends not just on the genetic variation but on the amountof the enzyme that the person produces. It's reported in theNovember Nature Genetics under the title: "The effect of the humanserum paraoxonase polymorphism is reversed with diazoxon, somanand sarin."

Some people have in their blood an inherited PON1 variantcontaining the amino acid, arginine; others, glutamine. For parathion,the former acts quickly; the latter, slowly.

The article's senior author, medical geneticist Clement Furlong, toldBioWorld Today: "We showed that the effect of the PON1polymorphism is reversed for the hydrolysis of diazoxon, soman andespecially sarin. This changed the view of which PON1 isoform isconsidered to be protective."

Furlong, who is at the University of Washington in Seattle, studiedthe genomic enzymic endowment of 92 Hispanic farm workers, priorto pesticide exposure, during the growing season. He and his co-authors found that 16 percent of their Hispanic cohorts werehomozygous for the arginine variant, compared with only ninepercent for people of Northern European origin.

They concluded that "on average, humans may be better able todetoxicate diazinon [EPA-approved against fire ants] thanchlorpyrifos [an anti-cinch-bug and tick insecticide], or parathion."

But when, following the Tokyo subway release, Furlong and his teamlooked into the relative anti-sarin efficiencies of paraoxonase's twoamino-acid polymorphisms, they found that the glutamine alleleworked nearly 10 times faster than the arginine _ just the opposite oftheir finding for parathion.

"The genotype alone doesn't tell you everything you need to knowabout this polymorphism," Furlong pointed out. "You need to knowthe genotype, but also how much protein is made from each PON1gene.

Paraoxenase In The First-Aid Kit

One of the practical applications of his research, Furlong said,"would be knowing which enzyme to use in case of anorganophosphate poisoning.

"For parathion exposure, you'd want to give him or her the arginineenzyme. We've shown in animal-model experiments that if you injectenzyme post-exposure, you can protect the brain and diaphragmcholinesterase. Injected enzyme works either pre-exposure or evenpost-exposure.

"Now for something as nasty as sarin," he added, "you'd want to geta lot of enzyme in, in a hurry. An intravenous injection ofparaoxenase would give you very rapid increase. If you shoot itintramuscularly, it stays steady in the bloodstream for a couple ofdays, like controlled drug release."

Furlong emphasized that "The military should absolutely have a bigstockpile of recombinant paroxonase. For their purposes, as far assarin and soman poisoning are concerned, the glutamine isoform isthe one of choice."

He did his post-Tokyo sarin studies in collaboration with co-authorClarence Broomfield of the U.S. Army chemical defense researchgroup at the Aberdeen Proving Grounds, in Maryland. "I haven'ttalked to the Pentagon directly," Furlong said, "but I have made thefolks at Walter Reed Army Medical Center, in Washington, aware ofthese data, and if we establish contact with the Pentagon people,we'll be happy to help them."

Meanwhile, besides continuing these studies, Furlong "aims to makerecombinant paraoxonases as inexpensively as we can."

He pointed out "another important finding: This enzyme is doing itspoison-detoxicating job _ hydrolyzing these organophosphates _ asa hobby. Its real role," he explained, "is in lipid metabolism with theHDL `good cholesterol' particle. A group at the University ofCalifornia, Los Angeles, he observed, "has done a very nice jobshowing that platelet-activating acetyl hydrolase and paraoxonasework together in cleaning up oxidized phospholipids.

In an editorial accompanying the Nature Genetics article,pharmacologist Bert LaDu of the University of Michigan MedicalSchool at Ann Arbor, observed: "There are many instances whereenzyme variants differing by a single amino acid substitution . . .have shown widely differing activities toward the same substrate."LaDu recalled as a case in point, "a mutation in the reversetranscriptase of HIV-1 that confers ddI drug resistance induces AZTsensitivity."n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.

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