1.   Richard C. Stevens <http://www.pnas.org/search?author1=Richard+C.++Stevens&sortspec=date&submit=Submit> ,

2.   Stephanie M. Suzuki <http://www.pnas.org/search?author1=Stephanie+M.++Suzuki&sortspec=date&submit=Submit> ,

3.   Toby B. Cole <http://www.pnas.org/search?author1=Toby+B.++Cole&sortspec=date&submit=Submit> ,

4.   Sarah S. Park <http://www.pnas.org/search?author1=Sarah+S.++Park&sortspec=date&submit=Submit> ,

5.   Rebecca J. Richter <http://www.pnas.org/search?author1=Rebecca+J.++Richter&sortspec=date&submit=Submit> , and

6.   Clement E. Furlong <http://www.pnas.org/search?author1=Clement+E.++Furlong&sortspec=date&submit=Submit> * <http://www.pnas.org/content/early/2008/08/15/0805865105.abstract?etoc#corresp-1> 

+ <http://www.pnas.org/content/early/2008/08/15/0805865105.abstract?etoc> Author Affiliations

1.    Division of Medical Genetics, Departments of Medicine and Genome Sciences, University of Washington, Seattle, WA 98195

1.     Communicated by Arno G. Motulsky, University of Washington, Seattle, WA, June 19, 2008 (received for review May 12, 2008)

Abstract

The high-density lipoprotein-associated enzyme paraoxonase 1 (PON1) hydrolyzes lactones, aromatic esters, and neurotoxic organophosphorus (OP) compounds, including insecticide metabolites and nerve agents. Experiments with mice lacking PON1 (PON1−/− mice) have established that plasma PON1 protects against chlorpyrifos/chlorpyrifos-oxon and diazinon/diazoxon (DZO) exposure but does not protect against parathion/paraoxon or nerve agents. The catalytic efficiency of PON1 determines whether or not it will protect against a given OP exposure. Expression of active recombinant human PON1 (rHuPON1) in Escherichia coli provides a system in which PON1 can be engineered to achieve a catalytic efficiency sufficient to protect against or treat specific OP exposures. Here, we describe the generation of highly purified engineered rHuPON1K192 that protects against DZO exposure when injected into PON1−/− mice. The injected rHuPON1 is nontoxic, persists in serum for at least 2 days after injection, and provides protection against DZO exposures of at least three times the median lethal dose value.

·       Escherichia coli-produced human PON1 <http://www.pnas.org/search?fulltext=Escherichia+coli-produced+human+PON1&sortspec=date&submit=Submit> 

·  engineered PON1 <http://www.pnas.org/search?fulltext=engineered+PON1&sortspec=date&submit=Submit> 

·         therapeutic PON1 <http://www.pnas.org/search?fulltext=therapeutic+PON1&sortspec=date&submit=Submit> 

Footnotes

·         *To whom correspondence should be addressed at: Division of Medical Genetics, Department of Medicine, Box 357720, University of Washington, Seattle, WA 98195-7720. E-mail: clem@u.washington.edu <mailto:clem@u.washington.edu&gt; 

·         Author contributions: R.C.S., S.M.S., T.B.C., and C.E.F. designed research; R.C.S., S.M.S., T.B.C., S.S.P., and R.J.R. performed research; R.C.S., S.M.S., T.B.C., R.J.R., and C.E.F. analyzed data; and R.C.S., S.M.S., T.B.C., R.J.R., and C.E.F. wrote the paper.

·         The authors declare no conflict of interest.

·         © 2008 by The National Academy of Sciences of the USA