Linked Life Data

10076534

Source:http://linkedlifedata.com/resource/pubmed/id/10076534

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
1999-3-30
pubmed:abstractText
The contribution of carboxylesterase (CarbE) to the development of tolerance to the organophosphorus anticholinesterase (OP-ANTIChE) paraoxon (diethyl p-nitrophenyl phosphate) was investigated in rats. Daily injections (20 days) of paraoxon (0.09 mg/kg) led to a cumulative dose that was 9.0-fold higher than the acute ED50 of 0.20 mg/kg, s.c. During this period, the rats did not demonstrate visible signs of cholinergic hyperactivity nor did they die, despite the persistence of critically reduced brain acetylcholinesterase (AChE) activity (20-30% of control). In addition, none of these rats died following the administration of a dose of carbachol (3.1 mg/kg, i.p.) that was an LD90 in untreated rats. Daily treatment with the CarbE inhibitors CBDP [2-(o-cresyl)-4H-1,3,2-benzodioxaphosphorin-2-oxide] (2 mg/kg, s.c.) or iso-OMPA (tetraisopropylpyrophosphoramide) (3 mg/kg, i.p.) followed by paraoxon (0.09 mg/kg, s.c.) 60 min later prevented the development of tolerance to paraoxon, since signs of cholinergic hyperactivity were observed and rats died on day 4 of the combined treatment. In tolerant rats, one-time CBDP or iso-OMPA pretreatment increased toxicity to paraoxon, causing the death of all rats within 60 min. The increase in paraoxon toxicity was correlated with inhibition of a plasma CarbE, with high affinity toward alpha-naphthyl acetate (alpha-NA) and to the inhibitors CBDP, iso-OMPA, and paraoxon. Inhibition of a plasma CarbE with high affinity toward p-nitrophenyl acetate (p-NPA) and low affinity to the above inhibitors did not potentiate paraoxon toxicity significantly. Neither the liver CarbEs, which showed high affinity to iso-OMPA, nor the inhibition of butyrylcholinesterase (BuChE) by iso-OMPA in plasma and liver potentiated paraoxon toxicity. By eliminating plasma CarbE (alpha-NA) as potential binding sites for paraoxon with either CBDP or iso-OMPA, paraoxon can exert its toxicity to a greater extent at its specific target site, the functionally important AChE at cholinergic synapses. It is concluded that plasma CarbE (alpha-NA) provided a significant protection against paraoxon intoxication and that the inhibition of this enzyme prevented the tolerance development seen with repeated paraoxon treatments.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0006-2952
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
55
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1419-26
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:10076534-Acetylcholinesterase, pubmed-meshheading:10076534-Animals, pubmed-meshheading:10076534-Brain, pubmed-meshheading:10076534-Butyrylcholinesterase, pubmed-meshheading:10076534-Carboxylesterase, pubmed-meshheading:10076534-Carboxylic Ester Hydrolases, pubmed-meshheading:10076534-Cholinesterase Inhibitors, pubmed-meshheading:10076534-Diarrhea, pubmed-meshheading:10076534-Drug Synergism, pubmed-meshheading:10076534-Drug Tolerance, pubmed-meshheading:10076534-Enzyme Inhibitors, pubmed-meshheading:10076534-Fasciculation, pubmed-meshheading:10076534-Kinetics, pubmed-meshheading:10076534-Male, pubmed-meshheading:10076534-Muscle, Skeletal, pubmed-meshheading:10076534-Organophosphorus Compounds, pubmed-meshheading:10076534-Paraoxon, pubmed-meshheading:10076534-Rats, pubmed-meshheading:10076534-Rats, Sprague-Dawley, pubmed-meshheading:10076534-Salivation, pubmed-meshheading:10076534-Seizures, pubmed-meshheading:10076534-Tetraisopropylpyrophosphamide, pubmed-meshheading:10076534-Tremor
pubmed:year
1998
pubmed:articleTitle
Prevention of tolerance to the organophosphorus anticholinesterase paraoxon with carboxylesterase inhibitors.
pubmed:affiliation
Department of Pharmacology and Neurology, Vanderbilt Univeristy School of Medicine, Nashville, TN 37232, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.