HUMAN SERUM PARAOXONASE

1. Human serum paraoxonase (PON1) is a Ca2+-dependent 45-kDa glycoprot ein that is associated with high density lipoprotein (HDL). 2. PON1 hy drolyzes organophosphate (OP) insecticides and nerve gases and is resp onsible for determining the selective toxicity of these compounds in m ammals. 3. PON1 has two genetic polymorphisms giving rise to amino aci d substitutions at positions 55 and 192, The position 192 polymorphism is the major determinant of the PON1 activity polymorphism. However, the position-55 polymorphism also modulates activity. 4. Genotyping in dividuals for both PON1 polymorphisms may provide a method for identif ying those most at risk of OP poisoning. The effect of the PON1 polymo rphisms on activity may explain why some Gulf War veterans have develo ped Gulf War syndrome and some have not, despite similar OP exposure. 5. PON1 may also be a determinant of resistance to the development of atherosclerosis by protecting lipoproteins against oxidative modificat ion, perhaps by hydrolyzing phospholipid hydroperoxides. 6. The PON1 p olymorphisms are important in determining the capacity of HDL to prote ct low density lipoprotein against oxidative modification in vitro, wh ich may explain the relation between the PON1 alleles and coronary hea rt disease in case control studies. GEN PHARMAC 31;3:329-336, 1998. (C ) 1998 Elsevier Science Inc.