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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.
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{at}u.washington.edu
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
Engineered recombinant human paraoxonase 1 (rHuPON1) purified from Escherichia coli protects against organophosphate poisoning
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