Adenovirus-transduced human butyrylcholinesterase in mouse blood functions as a bioscavenger of chemical warfare nerve agents
| Autor: | Oksana Lockridge, Nageswararao Chilukuri, Robert C. diTargiani, Ellen G. Duysen, Ashima Saxena, Kalpana Parikh, Bhupendra P. Doctor |
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| Rok vydání: | 2009 |
| Předmět: |
Protein subunit
Soman law.invention Adenoviridae Mice law Transduction Genetic medicine Animals Humans Tissue Distribution Chemical Warfare Agents Gene Butyrylcholinesterase Nerve agent Pharmacology Mice Knockout Kidney Salivary gland Chemistry Molecular biology Recombinant Proteins medicine.anatomical_structure Biochemistry Toxicity Recombinant DNA Molecular Medicine Cholinesterase Inhibitors medicine.drug |
| Zdroj: | Molecular pharmacology. 76(3) |
| ISSN: | 1521-0111 |
| Popis: | Human serum butyrylcholinesterase (Hu BChE) is a promising therapeutic against the toxicity of chemical warfare nerve agents. We have showed previously that recombinant (r) Hu BChE can be expressed at very high levels, 400 to 600 U/ml in mouse blood, by delivering the Hu BChE gene using adenovirus (Ad). Here, we report the biochemical properties of the Ad-expressed full-length and truncated rHu BChE in mouse blood. The molecular sizes of the full-length rHu BChE subunit and its oligomers were similar to those of native Hu BChE, although only a small portion of the full-length rHu BChE subunit underwent assembly into dimers and tetramers. As expected, Ad containing the truncated Hu BChE gene transduced the expression of monomeric rHu BChE only. Compared with 415 U of rHu BChE per milliliter in blood, tissues including liver, lung, heart, brain, kidney, muscle, intestine, diaphragm, salivary gland, and fat expressed10 U/g of rHu BChE activity. Ad-expressed rHu BChE in mouse blood neutralized soman and O-ethyl S-2-N,N-diisopropylaminoethyl methylphosphonothiolate at rates similar to those of native Hu BChE and rHu BChE expressed in vitro. Because the expression of rHu BChE rapidly decreased 6 days after virus administration, sera were assayed for the presence of anti-Hu BChE antibodies. Anti-Hu BChE antibodies were detected on day 7 and in increased amounts thereafter, which coincided with the loss of Hu BChE expression in sera. In conclusion, the delivery of Hu BChE gene using Ad can be a promising strategy that can provide protection against multiple lethal doses of chemical warfare nerve agents in vivo. |
| Databáze: | OpenAIRE |
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