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Contents
Abstract 13
Chapter 1. Introduction 17
1.1. Obesity 17
1.2. Tat polypeptides 18
1.3. Radioiodinaton 20
1.4. IODO-GEN Method 23
1.5. Interspecies Scaling 26
Chapter 2. Aims 28
Chapter 3. Materials and Methods 29
3.1. Materials 29
3.2. Expression of Recombinant GST-TatdMt Fusion Protein and Purification 30
3.3. Radioiodination of GST-TatdMt 32
3.4. BCA-Protein Assay 33
3.5. Gamma Counting Procedures 33
3.6. Pharmacokinetics of 125I-GST-TatdMt in Mice(이미지참조) 34
3.6.1. Animals 34
3.6.2. Pharmacokinetics of 125I-GST-TatdMt in Mice after Intravenous Bolus Injection(이미지참조) 34
3.6.3. Pharmacokinetics of 125I-GST-TatdMt in Mice after Intraperitoneal Injection(이미지참조) 35
3.6.4. Pharmacokinetics of 125I-GST-TatdMt in Mice after Oral Administration(이미지참조) 36
3.6.5. Determination of Tissue Distribution of 125I-GST-TatdMt in Mice after Intravenous Injection(이미지참조) 36
3.6.6. Data Analysis 37
3.7. Pharmacodynamic Study of GST-TatdMt in Mice 39
3.7.1. Animals 39
3.7.2. Anti-Obesity Effect of GST-TatdMt after Intraperitoneal and Oral Administration 41
3.7.3. Blood Sampling, Tissue Collection and Biochemical Measurements 41
3.7.4. Data analysis 42
Chapter 4. Results and Discussion 43
4.1. Radioiodination and Determination of Total Radioactivity 43
4.2. Pharmacokinetics of 125I-GST-TatdMt in Mice after Intravenous Bolus Injection(이미지참조) 47
4.3. Pharmacokinetics of 125I-GST-TatdMt in Mice after Intraperitoneal Injection(이미지참조) 52
4.4. Pharmacokinetics of 125I-GST-TatdMt in Mice after Oral Administration(이미지참조) 56
4.5. Determination of Tissue Distribution of 125I-GST-TatdMt in Mice after Intravenous Injection(이미지참조) 60
4.6. Anti-Obesity Effect of GST-TatdMt after Oral Administration 66
4.7/4.6. Anti-Obesity Effect of GST-TatdMt after Intraperitoneal Injection 73
Chapter 5. Summary and Conclusions 80
Chapter 6. References 86
국문요약 94
Table 1. Composition of experimental diets 40
Table 2. Pharmacokinetic parameters of 125I-GST-TatdMt obtained in mice after i.v. injection at a dose of 652.7 nCi (102.3 ㎍ protein)(n=3-6)(이미지참조) 50
Table 3. Mean pharmacokinetic parameters of 125I-GST-TatdMt obtained after i.v. injection to mice (652.7 nCi, 102.3 ㎍ protein) and rats (4206.9 nCi, 73.2 ㎍ protein) and predicted pharmacokinetic parameter for human (70 kg)(이미지참조) 51
Table 4. Pharmacokinetic parameters of 125I-GST-Tatdmt obtained in mice after i.p. injection at a dose of 652.7 nCi (102.3 ㎍ protein)(n=3-5 at each sampling time)(이미지참조) 55
Table 5. Pharmacokinetic parameters of 125I-GST-TatdMt obtained in mice after oral administration at a dose of 652.7 nCi (102.3 ㎍ protein)(n=3-5 at each sampling time)(이미지참조) 59
Table 6. Pharmacokinetic parameters of 125I-GST-TatdMt in various organs obtained after i.v. Injection to mice at a dose of 652.7 nCi (102.3 ㎍ protein)(n=3-6 at each sampling time)(이미지참조) 64
Table 7. Pharmacokinetic parameters of 125I-GST-TatdMt in various organs obtained after i.v. Injection to mice at a dose of 652.7 nCi (102.3 ㎍ protein)(n=3-6 at each sampling time)(이미지참조) 65
Table 8. Body weight changes in mice treated with GST-TatdMt by multiple oral administration (2 mg/kg/head or 4 mg/kg/head) once a day for 15 days (mean ± S.E.) 69
Table 9. Average daily food intake and water consumption during multiple oral administration of GST-TatdMt (2 mg/kg/head and 4 mg/kg/head) to mice once a day for 15 days (mean ± S.E.) 70
Table 10. Changes in total fat fad and liver weight per gram of body weight (BW) of mice treated with GST-TatdMt by multiple oral administration (2 mg/kg/head and 4 mg/kg/head) once a day for 15 days (mean ± S.E.) 71
Table 11. Plasma biochemical parameters in mice treated with GST-TatdMt by multiple oral administration (2 mg/kg/head and 4 mg/kg/head) once a day for 15 days (mean ± S.E.) 72
Table 12. Body weight changes in mice treated with GST-TatdMt by multiple i.p. injection (2 mg/kg/head or 4 mg/kg/head) once a day for 15 days (mean ± S.E.) 76
Table 13. Average daily food intake and water consumption during multiple i.p. injection of GST-TatdMt (2 mg/kg/head or 4 mg/kg/head) once a day for 15 days (mean ± S.E.) 77
Table 14. Changes in total fat fad and liver weight per gram of body weight (BW) of mice treated with GST-TatdMt by multiple i.p. injection (2 and 4 mg/kg/head) once a day for 15 days (mean ± S.E.) 78
Table 15. Plasma biochemical parameters in mice treated with GST-TatdMt by multiple i.p. injection (2 mg/kg/head or 4 mg/kg/head) once a day for 15 days (mean ± S.E.) 79
Figure 1. Radioiodination of tyrosine and histidine residues in peptides by H₂OI+.(이미지참조) 22
Figure 2. Chemical structure of IODO-GEN (1,3,4,6,-tetrachloro-3α,6α-diphenylglycouril). 24
Figure 3. A schematic diagram of the iodination by the IODO-GEN method. 25
Figure 4. Fractional radioactivity vs. time profile obtained by a Sephadex G-25 column (mobile phase, 10 mM PBS, pH 7.4; flow rate, 0.65 ml/min). 44
Figure 5. A representative standard curve used in the determination of GST-TatdMt protein concentration (y = 0.0008x-0.0118, r² = 0.9971). 45
Figure 6. A representative standard curve used in the determination of radioactivity from biological samples (y = 422.3x-430.9, r² = 1.000). 46
Figure 7. Average total radioactivity in the whole blood after i.v. injection of 125I-GST-TatdMt (652.7 nCi, 102.3 ㎍ protein) to mice (n=3 - 6 at each sampling time)(Mean ± S.E.).(이미지참조) 48
Figure 8. Interspecies correlation between the body weight and the pharmacokinetic parameters of(A) Cls (y = 61.83x0.92) and (B) Vss (y = 1.13x1.15).(이미지참조) 49
Figure 9. Average total radioactivity in the whole blood after i.p. injection of 125I-GST-TatdMt (652.7 nCi, 102.3 ㎍ protein) to mice (n=3-5 at each sampling time)(Mean ± S.E.).(이미지참조) 53
Figure 10. Simulated total radioactivity in the whole blood as a function of times after multiple i.p. injection of 125I-GST-TatdMt (652.7 nCi, 102.3 ㎍ protein) to every 24 hr for 16 days.(이미지참조) 54
Figure 11. Average total radioactivity in the whole blood after oral administration of 125I-GST-TatdMt (652.7 nCi, 102.3 ㎍ protein) to mice (n=3-5 at each sampling time)(Mean ± S.E.).(이미지참조) 57
Figure 12. Simulated total radioactivity in the whole blood as a function of times after multiple oral administration of 125I-GST-TatdMt (652.7 nCi, 102.3 ㎍ protein) to mice every 24 hr for 16 days.(이미지참조) 58
Figure 13. Average total radioactivity vs. time profiles in liver, spleen, kidney, and testis after i.v. injection of 125I-GST-TatdMt (652.7 nCi,102.3 ㎍ protein) to mice (n = 3 - 6 at each sampling time)(Mean ± S.E.).(이미지참조) 61
Figure 14. Average total radioactivity vs. time profiles in adipose, heart, lung, and skin after i.v. injection of 125I-GST-TatdMt (652.7 nCi, 102.3 ㎍ protein) to mice (n = 3 - 6 at each sampling time)(Mean ± S.E.).(이미지참조) 62
Figure 15. Average total radioactivity vs. time profiles in muscle, brain, stomach, and intestine after i.v. injection of 125I-GST-TatdMt (652.7 nCi, 102.3 ㎍ protein) to mice (n = 3 - 6 at each sampling time)(Mean ± S.E.).(이미지참조) 63
Figure 16. Body weight changes in mice after multiple oral administration of GST-TatdMt (2 mg/kg/head or 4 mg/kg/head) once a day for 15 days(mean±S.E.). 68
Figure 17. Body weight changes in mice after multiple i.p. injection of GST-TadMt (2 mg/kg/head or 4 mg/kg/head) once a day for 15 day (mean ± S.E.). 75
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