Gene transfer of cocaine hydrolase suppresses cardiovascular responses to cocaine in rats
Gao, Y; Atanasova, E; Sui, N; Pancook, JD; Watkins, JD; Brimijoin, S
2005
发表期刊MOLECULAR PHARMACOLOGY
ISSN0026-895X
文章类型Article
卷号67期号:1页码:204-211
摘要We previously found that injection of a cocaine hydrolase (CocE) engineered from human butyrylcholinesterase will transiently accelerate cocaine metabolism in rats while reducing physiological and behavioral responses. To investigate more extended therapeutic effects, CocE cDNA was incorporated into a replication-incompetent type-5 adenoviral vector with a cytomegalovirus promoter. In rats dosed with this agent (2.2 × 109 plaque-forming units), the time course of expression was characterized by reverse transcription polymerase chain reaction for CocE mRNA and by radiometric assay for enzyme activity. Liver and plasma showed comparable expression, beginning 2 days after vector administration and peaking between 5 and 7 days. Plasma CocE content was up to 100 mU/ml, with total cocaine hydrolyzing activity 3000-fold greater than in “empty vector” or untreated controls. This level of expression approximated that found immediately after i.v. injection of purified hydrolase, 3 mg/kg, a dose that shortened cocaine halflife and blunted cardiovascular effects. Sucrose density gradient analysis showed that 96% of the circulating CocE activity was associated with tetrameric enzyme forms, expected to be stable in vivo. Consistent with this expectation, CocE from vector-treated rats showed a plasma t1/2 of 33 h when reinjected into naive rats. Transduction of another mutant butyrylcholinesterase, Applied Molecular Evolution mutant 359 (AME359), caused plasma cocaine hydrolase activity to rise 50,000-fold. At the point of peak AME359 expression, cocaine was cleared from the blood too rapidly for accurate measurement, and pressor responses to the injection of drug were greatly impaired.; We previously found that injection of a cocaine hydrolase (CocE) engineered from human butyrylcholinesterase will transiently accelerate cocaine metabolism in rats while reducing physiological and behavioral responses. To investigate more extended therapeutic effects, CocE cDNA was incorporated into a replication-incompetent type-5 adenoviral vector with a cytomegalovirus promoter. In rats dosed with this agent (2.2 x 10(9) plaque-forming units), the time course of expression was characterized by reverse transcription polymerase chain reaction for CocE mRNA and by radiometric assay for enzyme activity. Liver and plasma showed comparable expression, beginning 2 days after vector administration and peaking between 5 and 7 days. Plasma CocE content was up to 100 mU/ml, with total cocaine hydrolyzing activity 3000-fold greater than in "empty vector" or untreated controls. This level of expression approximated that found immediately after i.v. injection of purified hydrolase, 3 mg/kg, a dose that shortened cocaine half-life and blunted cardiovascular effects. Sucrose density gradient analysis showed that 96% of the circulating CocE activity was associated with tetrameric enzyme forms, expected to be stable in vivo. Consistent with this expectation, CocE from vector-treated rats showed a plasma t(1/2) of 33 h when reinjected into naive rats. Transduction of another mutant butyrylcholinesterase, Applied Molecular Evolution mutant 359 (AME(359)), caused plasma cocaine hydrolase activity to rise 50,000-fold. At the point of peak AME(359) expression, cocaine was cleared from the blood too rapidly for accurate measurement, and pressor responses to the injection of drug were greatly impaired.
关键词human butyrylcholinesterase vectors acetylcholinesterase cholinesterases transporters pharmacology expression progress abuse
学科领域生理心理学/生物心理学
收录类别SCI
语种英语
WOS记录号WOS:000225865200023
引用统计
被引频次:34[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.psych.ac.cn/handle/311026/5437
专题中国科学院心理研究所回溯数据库(1956-2010)
作者单位1.Mayo Clin & Mayo Fdn, Dept Mol Pharmacol, Rochester, MN 55905 USA
2.Eli Lilly Appl Mol Evolut, San Diego, CA USA
3.Chinese Acad Sci, Inst Psychol, Beijing, Peoples R China
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GB/T 7714
Gao, Y,Atanasova, E,Sui, N,et al. Gene transfer of cocaine hydrolase suppresses cardiovascular responses to cocaine in rats[J]. MOLECULAR PHARMACOLOGY,2005,67(1):204-211.
APA Gao, Y,Atanasova, E,Sui, N,Pancook, JD,Watkins, JD,&Brimijoin, S.(2005).Gene transfer of cocaine hydrolase suppresses cardiovascular responses to cocaine in rats.MOLECULAR PHARMACOLOGY,67(1),204-211.
MLA Gao, Y,et al."Gene transfer of cocaine hydrolase suppresses cardiovascular responses to cocaine in rats".MOLECULAR PHARMACOLOGY 67.1(2005):204-211.
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