Original ArticlesRabbits possess a serum paraoxonase polymorphism similar to the human Q192RWatson, Catherine E.a,b; Draganov, Dragomir I.a; Billecke, Scott S.a; Bisgaier, Charles L.b; La Du, Bert N.aAuthor Information aDepartments of Pharmacology and Anesthesiology, University of Michigan, Ann Arbor, MI and bDepartment of Pharmacology, Esperion Therapeutics, Inc., Ann Arbor, MI, USA Received 26 July 2000; accepted 31 August 2000 Correspondence to C. Watson, Department of Pharmacology, Esperion Therapeutics, 3621 South State Street, 695 KMS Place, Ann Arbor, MI 48108, USA Tel: +1 734 332 0506; fax: +1 734 332 0516; e-mail: [email protected] Pharmacogenetics: March 2001 - Volume 11 - Issue 2 - p 123-134 Buy Abstract Serum paraoxonase (PON1) is a high-density lipoprotein (HDL)-associated enzyme that hydrolyses aromatic esters, organophosphates and lactones and can protect low-density lipoprotein (LDL) against oxidation. These properties are influenced by a well-characterized polymorphism (Q192R) in human PON1. We now report the identification and characterization of a phenotypically similar, but genetically distinct polymorphism in rabbit PON1. This polymorphism in rabbits was detected by phenotyping sera obtained from 16 inbred rabbit strains and 20 outbred New Zealand White rabbits by paraoxonase/arylesterase activity. The genetic basis of the rabbit polymorphism was determined by DNA sequencing and found to reside in a region distinct from the human Q192R and M55L polymorphisms. Three variant nucleotides within exon 4 (corresponding to P82S, K93E and S101G) were found to segregate with the observed rabbit PON1 phenotypes (rPON1A and rPON1B). The rPON1A and rPON1B proteins were purified and compared to the two human isoforms (192Q and 192R). The human and rabbit PON1s displayed similar characteristics with respect to physical properties and substrate specificity. However, rPON1A and rPON1B hydrolysed a variety of substrates at different rates. The rPON1A was also at least three-fold more efficient at protecting LDL from oxidation than rPON1B. Our characterization of a rabbit PON1 polymorphism provides useful insights into important functional residues in PON1. In addition, due to the observed similarities between the rabbit and human polymorphisms, the rabbit may serve as a good model to examine the effect of human PON1 polymorphisms in disease development. © 2001 Lippincott Williams & Wilkins, Inc.