EFFECT OF THE MOLECULAR POLYMORPHISMS OF HUMAN PARAOXONASE (PON1) ON THE RATE OF HYDROLYSIS OF PARAOXON

1 The hydrolysis of organophosphate pesticides (OF) and nerve gases by serum paraoxonase (PON1) is an important factor determining their tox icity to mammals including man. The PON1 gene contains 2 polymorphic s ites at amino acid positions 55 (L-->M) and 192 (G-->A, classically de fined as the A and B genotypes) which result in several alloenzymes of PON1 in human serum. 2 The 192 polymorphism has previously been shown to affect PON1 activity. We have investigated the effect of both poly morphisms on the hydrolysis of paraoxon by serum from 279 healthy huma n subjects. 3 The 55 polymorphism significantly influenced PON1 activi ty. MM homozygotes had over 50% less activity towards paraoxon compare d to the LL and LM genotypes regardless of the 192 genotype (P<0.001). 4 Multiple regression analysis indicated that the 192 polymorphism, 5 5 polymorphism and serum PON1 concentration were responsible for 46, 1 6 and 13% of the variation in PON1 activity, respectively (all P<0.001 ). None of the other parameters investigated significantly affected PO N1 activity. 5 Therefore both PON1 polymorphisms affect the hydrolysis of paraoxon. AA/MM and AB/MM individuals may be potentially more susc eptible to OP intoxication. 6 Genotyping individuals for both PON1 pol ymorphisms may provide a method for identifying those individuals at m ost risk of OP poisoning. The effect of PON1 polymorphisms on activity may also explain why some Gulf War Veterans have developed Gulf War S yndrome and some have not.