Gene transfer of cocaine hydrolase suppresses cardiovascular responses to cocaine in rats
文献类型：期刊论文
| 作者 | Gao, Y ; Atanasova, E; Sui, N; Pancook, JD; Watkins, JD; Brimijoin, S
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| 刊名 | MOLECULAR PHARMACOLOGY
 |
| 出版日期 | 2005 |
| 卷号 | 67期号:1页码:204-211 |
| 关键词 | human butyrylcholinesterase vectors acetylcholinesterase cholinesterases transporters pharmacology expression progress abuse |
| ISSN号 | 0026-895X |
| 文献子类 | Article |
| 英文摘要 | 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. |
| 学科主题 | 生理心理学/生物心理学 |
| 语种 | 英语 |
| WOS记录号 | WOS:000225865200023 |
| 公开日期 | 2011-08-22 |
| 源URL | [http://ir.psych.ac.cn/handle/311026/5437]  |
| 专题 | 心理研究所_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 |
| 推荐引用方式 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. |
入库方式： OAI收割
来源：心理研究所
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