Paraoxonase genetic polymorphisms

Mackness B, Mackness MI, Arrol S, Turkie W, Durrington PN. Effect of the human serum paraoxonase 55 and 192 genetic polymorphisms on the protection by high density lipoprotein against low density lipoprotein oxidative modification. FEB Lett 1998 423 57-60. 

Kondo, L, Yamamoto, M. (1998). Genetic polymorphism of paraoxonase 1 (PONl) and susceptibility to Parkinson s disease. Brain Res. 806 271-3. 

Similar results have been reported for polymorphisms at amino acid 55, with the PONl paraoxonase activity in blood serum from 55M (methionine) homozygotes reduced compared to either the 55L (leucine) homozygotes or the LM heterozygotes (Mackness et al, 1997). While it is intuitive that the rate of detoxification of a substrate would be dependent on the expression levels of these endogenous enzymes, the effects of the genetic polymorphisms suggest that catalytic efficiency is an equally important consideration. 

The human paraoxonase-1 (PONl) is a 45kDa calcium-dependent enzyme bound to high-density lipoprotein (HDL) particles, in association with other apolipoproteins. PON 1 shows a genetic polymorphism the most prominent determines the Q192R allozyme, which can have a substantial impact on PONl activity against OPs and arylesters (Smo-len et al, 1991) (Table 70.1). The enzyme was shown to be involved in the protection against atherosclerosis (Shih... 

LaDu BN Invited editorial the human serum paraoxonase/arylesterase polymorphism. Am J Hum Genet 43 227-229,1988 Landrigan PJ Pesticides and polychlorinated biphenyls (PCBs) an analysis of the evidence that they impair children s neurohehavioral development. Mol Genet Metah 73 11-17, 2001... 

Biological availability for neurotoxic responses is a complex problem for in vitro toxicology, because the availability of OP compounds to target cells i.s dependent on many variable factors. OP compound availability in v/vo is dependent on genetic polymorphisms of scrum proteins, such as paraoxonase-1. as well as on age and other serum protease activities (Costa et al.. 2003 Sklan et al.. 2(X)4)... 

Ginsberg, G., Neafsey, P, Hattis, D., et al., 2009. Genetic polymorphisms in paraoxonase 1 (PONl) population distribution of PONl activity. J. Toxicol. Environ. Health Part B 12,473-507. 

Singh, S., Kumar, V, Thakur, S., et al, 2011. Paraoxonase-1 genetic polymorphisms and susceptibility to DNA damage in workers occupationally exposed to organophosphate pesticides. Toxicol. Appl. Pharmacol. 252, 130-137. 

Davies, H.G., Richter, R.J., Keifer, M., Broomfield, C.A., Sowalla, J., Furlong, C.E. (1996). The effect of the human serum paraoxonase polymorphism is reversed with diazoxon, soman and sarin. Nat. Genet. 14 334-6. 

The susceptibility of a minority of the population may be explained by genetic variation in genes affecting OP metabolism. The best studied example is paraoxonase, an enzyme that inactivates OPs (Furlong, 2007 La Du et al, 2001). Paraoxonase polymorphism in humans is hypothesized to explain why some people are resistant to OP toxicity while others are susceptible. Another enzyme that may be involved in resistance to OP toxicity is butyrylcholinesterase. Butyrylcholinesterase scavenges OPs,... 

Brophy, V.H., Jampsa, R.L., Clendenning, J.B., McKinstry, L.A., Furlong, C.E. (2001b). Effects of S regulatory-region polymorphisms on paraoxonase gene (PONl) expression. Am. J. Hum. Genet. 68 1428-36. 

Mueller, R.F., Homung, S., Furlong, C.E., Anderson, J., Giblett, E.R., Motulsky, A.G. (1983). Plasma paraoxonase polymorphism a new enzyme assay, population, family biochemical and linkage studies. Am. J. Hum. Genet. 35 393-408. 

Smolen, A., Eckreson, H.W., Gan, K.N., Hailat, N., La Du, B.N. (1991). Characteristics of the genetically determined polymorphic forms of human serum paraoxonase/arylesterase. Drug. Metab. Dispos. 19 107-12. 

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