The effect of the human serum paraoxonase polymorphism is reversed with diazoxon, soman and sarin.
Many organophosphorus compounds (OPs) are potent cholinesterase inhibitors, accounting for their use as insecticides and, unfortunately, also as nerve agents. Each year there are approximately 3 million pesticide poisonings world-wide resulting in 220,00 deaths. In 1990, there were 1.36 million kg of chlorpyrifos, 4.67 million kg of diazinon and 1.23 million kg of ethyl parathion manufactured in the USA (data supplied by the USEPA). In addition to exposure risks during pesticide manufacturing, distribution and use, there are risks associated with the major international effort aimed at destroying the arsenals of nerve agents, including soman and sarin. The United States has pledged to destroy approximately 25,000 tons of chemical agents by the end of the decade. The high density lipoprotein (HDL)-associated enzyme paraoxonase (PON1) contributes significantly to the detoxication of several OPs (Fig. 1). The insecticides parathion, chlorpyrifos and diazinon are bioactivated to potent cholinesterase inhibitors by cytochrome P-450 systems. The resulting toxic oxon forms can be hydrolysed by PON1, which also hydrolyses the nerve agents soman and sarin (Fig. 1). PON1 is polymorphic in human populations and different individuals also express widely different levels of this enzyme. The Arg192 (R192) PON1 isoform hydrolyses paraoxon rapidly, while the Gln192 (Q191) isoform hydrolyses paraoxon slowly. Both isoforms hydrolyse chlorpyrifos-oxon and phenylacetate at approximately the same rate. The role of PON1 in OP detoxication is physiologically significant. Injected PON1 protects against OP poisoning in rodent model systems and interspecies differences in PON1 activity correlate well with observed median lethal dose (LD50) values. We report here a simple enzyme analysis that provides a clear resolution of PON1 genotypes and phenotypes allowing for a reasonable assessment of an individual's probable susceptibility or resistance to a given OP, extending earlier studies on this system. We also show that the effect of the PON1 polymorphism is reversed for the hydrolysis of diazoxon, soman and especially sarin, thus changing the view of which PON1 isoform is considered to be protective.
Department of Genetics, University of Washington, Seattle 98195-7360, USA.
H G
HG
Davies
R J
RJ
Richter
M
M
Keifer
C A
CA
Broomfield
J
J
Sowalla
C E
CE
Furlong
D043303:Aryldialkylphosphatase; D002619:Chemical Warfare Agents / Q000378:metabolism / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics; D004950:Esterases / Q000097:blood* / Q000187:drug effects / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007527:Isoenzymes; D009943:Organophosphorus Compounds / Q000378:metabolism* / Q000494:pharmacology; D011110:Polymorphism, Genetic; D012524:Sarin / Q000378:metabolism* / Q000494:pharmacology; D012999:Soman / Q000378:metabolism* / Q000494:pharmacology; D013020:South America
D002619:Chemical Warfare Agents; D007527:Isoenzymes; D009943:Organophosphorus Compounds; D012999:Soman; C000912:diazoxon; D012524:Sarin; D004950:Esterases; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human