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Pharmacogenetics of paraoxonases: a brief review

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Abstract

The human paraoxonase (PON) gene family consists of three members, PON1, PON2, and PON3, aligned next to each other on chromosome 7. By far the most-studied member of the family is the serum paraoxonase 1 (PON1), a high-density lipoprotein-associated esterase/lactonase. Early research focused on its capability to hydrolyze toxic organophosphates, and its name derives from one of its most commonly used in vitro substrates, paraoxon. Studies in the last 2 decades have demonstrated PON1’s ability to protect against atherosclerosis by hydrolyzing specific derivatives of oxidized cholesterol and/or phospholipids in oxidized low-density lipoprotein and in atherosclerotic lesions. Levels and genetic variability of PON1 influence sensitivity to specific insecticides and nerve agents, as well as the risk of cardiovascular disease. More recently, the other two members of the PON family, PON2 and PON3, have also been shown to have antioxidant properties. A major goal in present research on the paraoxonases is to identify their natural substrates and to elucidate the mechanism(s) of their catalytic activities.

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Notes

  1. The numbering of the amino acid residues in this review is in accord with the recommendations of the Third International Meeting on Esterases Reacting with Organophosphorus Compounds (Dubrovnik, Croatia, April 1998) (La Du et al. 1999b) and starts with the initial Met. Thus the numbering in the text may differ by +1 with some of the original references in which the numbering starts from Ala2 (the first amino acid in the secreted protein). Also we refer to one of the PON1 promoter polymorphisms as T(−108)C rather than −107 number used by R.W. James’ group.

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Acknowledgements

We gratefully acknowledge the Michigan Life Sciences Corridor Fund #001796 for supporting our recent PON research.

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  1. Department of Pharmacology, MSRB 3, Room 1301, University of Michigan, Ann Arbor, MI 48109-0632, USA

    D. I. Draganov & B. N. La Du

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Draganov, D.I., La Du, B.N. Pharmacogenetics of paraoxonases: a brief review. Naunyn-Schmiedeberg's Arch Pharmacol 369, 78–88 (2004). https://doi.org/10.1007/s00210-003-0833-1

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