University of Washington
I-204 Health Sciences Building
Seattle, WA 98195-7360
Phone: (206) 543-1193
FAX: (206) 543-0754
Dr. Furlong's laboratory is investigating the functional genomics of the polymorphic, HDL-associated enzyme human serum paraoxonase (PON1). The main known physiological function of this protein is to metabolize toxic oxidized lipids and protect against vascular disease.
In addition to this role, PON1 is also important in detoxifying organophosphorus Insecticides such as chlorpyrifos and diazinon are bioactivated to highly toxic oxon forms by the cytochrome P450 systems. The toxic oxons are potent inhibitors of acetylcholinesterase. These oxons are hydrolyzed by PON1. Direct testing of PON1's protective effects against organophosphate poisoning in a mouse model system verifies the role of PON1 in detoxication in vivo. PON1 exhibits a substrate-dependent polymorphism in human populations.
At least two allelic forms of the enzyme have been
observed. One alloform (PON1R192) hydrolyzes chlorpyrifos oxon (the toxic metabolite
of chlorpyrifos or Dursban®) with a high catalytic efficiency and the other (PON1Q192)
with a lower catalytic efficiency. Both PON1 alloforms detoxify diazoxon (the active
metabolite of diazinon) with equal efficiency.
As noted above, PON1 appears to play an important role in metabolizing toxic oxidized
lipids. A number of recent studies have reported that the R192 variant of this protein
is a risk factor for coronary artery disease. Our own studies carried out in collaboration
with Dr. Gail Jarvik have shown that low PON1 levels are a risk factor for carotid artery
disease. The functions of two related proteins, PON2 and PON3 are also being investigated.
A second interest of Dr. Furlong's laboratory is the development of surface plasmon resonance
(SPR) biosensors that have a broad range of applications in the fields of medicine, biotechnology
and environmental monitoring. For monitoring applications, the sensors are capable of detecting
small molecules such as hormones, insecticides, nerve agents as well as larger analytes including
toxic proteins, viruses and microbes. As general laboratory instruments, the SPR biosensor
systems are capable of monitoring in real time, biomolecular interactions such as the interaction
of transcription factors with specific DNA sequences, interactions of protein subunits with
complexes and receptor/ligand interactions.
Investigator: Dr. Furlong is a Research Professor of Medicine (Medical Genetics) and Genome Sciences.
Davies H, Richter RJ, Keifer M, Broomfield C. Sowalla J, Furlong CE. The effect of the human serum paraoxonase polymorphism is reversed with diazoxon, soman and sarin. Nature Genetics 14:334-336, 1996.
Shih DM, Gu L, Xia YR, Navab M, Li WF, Hama S, Castellani LW, Furlong CE, Costa LG, Fogelman AM, Lusis AJ. Serum paraoxonase knockout mice are susceptible to organophosphate insecticides and lipoprotein oxidation. Nature 394:284-287, 1998.
Li WF, Costa LG, Richter RJ, Hagen T, Shih DM, Tward A, Lusis AJ, Furlong CE. Catalytic efficiency determines the efficacy of PON1 for detoxifying organophosphates. Pharmacogenetics 10:767-780, 2000.
Cole TB, Jampsa RL, Walter BJ, Arndt TL, Richter RJ, Shih DM, Tward A, Lusis AJ, Jack RM, Costa LG, Furlong CE. Expression of human paraoxonase (PON1) during development. Pharmacogenetics 13:357-364, 2003.
Jarvik GP, Jampsa R, Richter RJ, Carlson C, Rieder M, Nickerson D, Furlong CE. Novel paraoxonase (PON1) nonsense and missense mutations predicted by functional genomic assay of PON1 status. Pharmacogenetics 13:291-295, 2003.
Costa LG, Cole TB, Jarvik GP, Furlong CE. Functional Genomics of the Paraoxonase (PON1) Polymorphisms: Effects on Pesticide Sensitivity, Cardiovascular Disease, and Drug Metabolism. Ann Rev Med 54:371-392, 2003.
Naimushin AN, Soelberg SD, Nguyen D, Dunlap L, Barthalomew D, Elkind J, Melendez J, Furlong CE. Detection of Staphlococcus aureus enterotoxin B in femtomolar amounts by a miniature integrated two-channel SPR sensor. Biosens Bioelectron 17(6-7):573-84, 2002.
Naimushin AN, Soelberg SD, Bartholomew DU, Elkind JL, Furlong CE. A Portable Surface Plasmon Resonance (SPR) Sensor System with Temperature Regulation. Sensors and Actuators B 96:253-260, 2003.