1. ROLE OF PARAOXONASE IN DISEASES OTHER THAN ATHEROSCLEROSIS

2. WORLD WIDE USE OF ORGANO-PHOSPHATES
Insecticides, plasticiser, fire retardants, nerve gases and medicines.
Three pesticides alone account for over 7. 5 million kg of OP usage annually in the US
World wide production is estimated to be greater than 150 million kg/yr
World wide OP poisonings are three million/yr
with over 200,000 deaths

3. EXTREME USE OF OPs Saddaim Hussain used OPs Kurds Gulf War
Tokyo underground incident release of sarin
Problem is you make an OP with a toxicity 20X that of HCN gas in your garden shed
Sub-acute toxicity symptoms are undefined

4. CLASSSIFICATION OF ESTERASES
‘A’-ESTERASES (PARAOXONASE) detoxify Ops
‘B’-ESTERASES inhibited by OPs
Mode of action inhibit acetylcholinesterases in the nervous system so it prevents nerve transmission

5. PURIFIED PARAOXONASE INTO REDUCED THE TOXICITY OF OPs
RUSSELL MAIN (1960)
HE INJECTED PARTIALLY
PURIFIED PARAOXONASE INTO
RATS AND SHOWED THAT IT
REDUCED THE TOXICITY OF OPs

6. TOXICITY OF OPs BIRDS AND INSECTS HAVE NO PARAOXONASE
LD50(mg/kg) MAMMALS BIRDS
DIAZINON
DIMETHOATE
PRIMIPHOS-METHYL
PRIMPIHOS-ETHYL
BIRDS AND INSECTS HAVE
NO PARAOXONASE

7. KNOCKOUT MOUSE
PARAOXONASE KNOCKOUT MICE ARE RENDERED EXTREMELY SUSCEPIBLE TO OPs
THEREFORE SERUM PARAOXONASE IS EXTREMELY IMPORTANT IN MAMMALIAN METABOLISM OF OPs

8. PARAOXONASE (PON1)/ARYLESTERASE (EC 3.1.8.1)
43,000 daltons cDNA predicts 355 aas
Long arm of chromosome 7(q21-q22)
86% similarity between rabbit and human cDNA
Ca2+dependent
Located on HDL (subfraction containing apoA1 & clusterin
10-40 fold variation between individuals
No gender difference in enzyme activity has been reported

9. HUMAN SERUM PARAOXONASE (PON1) CODING REGION POLYMORPHISMS
Position 55
Methionine Leucine
M L
Position 192
Arginine Glutamine
Isoenzyme R Q
Only been found in humans

10. What is the role of PON in OP toxicity in man?
QUESTION?
What is the role of PON in OP toxicity in man?
HYPOTHESIS
We hypothesized that different PON isoforms may be important in determining OP toxicity

11. WHAT IS GULF WAR SYNDROME (GWS)
Likely to be a collection of different illnesses with similar symptoms including
Sleep problems Abdominal pain
Mood Swings Rashes Aching joints Headaches
Sensitivity to bright light Diarrhea
Short term memory loss Chronic fatigue
and many other symptoms

12. KNOWN EXPOSURES CHEMICAL & BIOLOGICAL AGENTS
EXPERIMENTAL DRUGS & VACCINES
DEPLETED URANIUM MUNITIONS
ENVIRONMENTAL EXPOSURES

13. STUDY GROUP & PARAMETERS MEASURED
152 GWV vs 152 CONTROLS
ALL THE GWVS HAD NEUROLOGICAL & HEALTH PROBLEMS
PON1 55 and 192 genotype(PCR/REs)
PON1 activity and PON1 mass (ELISA)
Butyrylcholinesterase
Apo A1 was a measure of HDL levels

14. * * * * BUTYRYLCHOLINESTERASE APOLIPOPROTEIN-A1
PARAOXON PON1 MASS * *
BUTYRYLCHOLINESTERASE APOLIPOPROTEIN-A1 * *
BBRC (2000) 276:

15. PON1 ACTIVITY * * * * * *
BBRC (2000)276:

16. PON1 CONCENTRATION * * * * *
BBRC (2000)276:

17. PON1 ALLELE FREQUENCIES
CONTROLS GWVs
PON1-55(L/M) / /0.35 NS
PON1-192(Q/R) / /0.29 NS

18. SERUM PON1 ACTIVITY
BBRC (2000)276:

19. SERUM PON1 CONCENTRATION
BBRC (2000)276:

20. SUMMARY
Low paraoxonase in Gulf War Veterans requires further investigation as it may be involved in the aetiology of the Gulf war syndrome complex

21. SCOPE (Susceptibility to Ops in agricultural workers)
OTHER STUDIES
SCOPE (Susceptibility to Ops in agricultural workers)
GULF WAR PHASE II
PON IN OP SUICIDES
PON IN OP TOXCITY IN GREENHOUSE SPRAYERS

22. ACKNOWLEDGMENTS
Mike Mackness
Paul Durrington
Larry Cammack
Eser Sozmen
Antonio Hernandez
Lourdes Rodriogo

23. PON Purification By Blue Agorose