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의약후보물질 최적화를 위한 독성평가 화학물질의 체내 대사체 구조 규명 (1 상 및 2 상 대사체 ) 화학물질의 체내 대사경로 연구 장내 미생물에 의한 화학물질 대사 연구

연구분야. 의약후보물질 최적화를 위한 독성평가 화학물질의 체내 대사체 구조 규명 (1 상 및 2 상 대사체 ) 화학물질의 체내 대사경로 연구 장내 미생물에 의한 화학물질 대사 연구 약 물 상호작용 연구. 보유기술. 간독성 및 면역독성 평가기술 (in vitro 및 in vivo) 대사체 구조 결정 (LC-MS) 약물 상호작용 평가 기술 간세포 분리 및 일차배양 기술 CYP 효소활성 측정기술. Metabolism. 연구분야 소개.

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의약후보물질 최적화를 위한 독성평가 화학물질의 체내 대사체 구조 규명 (1 상 및 2 상 대사체 ) 화학물질의 체내 대사경로 연구 장내 미생물에 의한 화학물질 대사 연구

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  1. 연구분야 • 의약후보물질 최적화를 위한 독성평가 • 화학물질의 체내 대사체 구조 규명 (1상 및 2상대사체) • 화학물질의 체내 대사경로 연구 • 장내 미생물에 의한 화학물질 대사 연구 • 약물 상호작용 연구 보유기술 • 간독성 및 면역독성 평가기술 (invitro 및 invivo) • 대사체구조 결정 (LC-MS) • 약물 상호작용 평가 기술 • 간세포 분리 및 일차배양 기술 • CYP 효소활성측정기술

  2. Metabolism 연구분야 소개 The elimination of xenobioticsdepends on their conversion to water-soluble metabolites by a process known as biotransformation, which is catalyzed by enzymes in the liver and other tissues.

  3. Phase Ⅰ and Phase Ⅱ Reactions

  4. UV Chromatograms of Rutaecarpine and its Metabolites Rutaecarpine without NGS Rutaecarpine with NGS Metabolites

  5. [M+H]+ m/z 169 EE+ 288 m/z 145 EE+ m/z 142 EE+ MS2 Spectra of Parent:Rutaecarpine m/z 120 EE+ Rutaecarpine [M+H]+ 288 m/z 185 OE+ 145.0 185.0 142.0 168.9 120.0

  6. Proposed Metabolic Pathway of Rutaecarpine in Human Liver Microsomes β-Glucuronidation and Sulfation β-Glucuronidation and Sulfation M1 CYP3A4 Only in vitro M5 M2 CYP3A4 CYP3A4/1A2/2C9 CYP1A2/2C9/3A4 CYP3A4/1A2/2C9 Rutaecarpine M3 M4 β-Glucuronidation and Sulfation

  7. Vehicle 200 mg/kg 500 mg/kg 1000 mg/kg 12hr 6 hr 24 hr 48 hr Acute effects of 1-BP on serum activity of ALT and histopathology of liver tissue X 100 magnification

  8. T-dependent antibody response to SRBC SRBCs (5×108) 4 days later After 30 min 1-BP treated BALB/c mice, po Sensitization, ip Single splenocyte Spleen 37oC 3 h later 0 h Splenocytes, SRBC, Complement (guinea pig) and 0.5% agar containing 0.05% DEAE-dextran Stereomaster plaque viewer, ×20 AFCs Splenocytes counting (Coulter counter) Cover glass (24×40 mm) Results: AFCs/106 spleen cells or AFCs/spleen (×103) Petri dish (100×15 mm)

  9. +H+ + 179.0 100 90 80 70 60 Relative Abundance 50 40 30 162.0 20 233.0 308.0 10 290.1 0 100 150 200 250 300 350 400 m/z CID Spectrum of Glutathione a b c [M+H-129]+ Glutathione [M+H]+ 308 a b c [M+H-146]+ [M+H-75]+ [M+H]+

  10. +H+ + +H+ + Fragmentation Mechanism and Proposed Structures of GSH a b c c Loss of neutral glycine [M+H]+ 308 [M+H-75]+233.0 b a Loss of amino glutamate Loss of glutamate [M+H-146]+162.0 [M+H-129]+ 179.0

  11. Propionic acid (Ether extract) NADPH- dependence 1-Bromopropane Propionaldehyde Propene (Volatile metabolite) NADPH- dependence 1,2-Propane-diol (Ether extract) NADPH- dependence Metabolism of 1-BP Excretion in urine GST N-acetyl-S-propyl cysteine S-propyl glutathione, m/z 350 Dehydrohalogenation (Enzyme-mediated) CYP GST GST CYP N-acetyl-S-(2-hydroxypropyl)cysteine α-hydroxylation S-(2’-Hydroxyl-1’-propyl) glutathione 3-Bromo-2-propanol CYP ALDH C3 oxidation GST Excretion in urine 3-Bromo-1-propanol N-acetyl-S-(3-hydroxypropyl)cysteine GST Barnsley et al., 1966, Jones and Walsh, 1979 Tachizawa et al., 1982 3-Bromopropionic acid N-acetyl-S-(2-carboxyethyl) cysteine

  12. Effects of 1-BP on content of GSH and formation of S-propyl GSH in liver and spleen: Dose-response

  13. Increased the serum ALT activity and tissue damage Spleen Suppressed the antibody response to SRBCs Suppressed the splenic intracellular IL-2 production stabilizer the wool chemical syntheses cleaning agent Overall ranking of toxicity: 1,2-DBP, 1,3-DBP > 1-BP >> 2-BP extraction solvents Liver spray form chemical intermediates Exposure Depletion of GSH Increased oxidative stress ? Dependent mechanism Glutathione S-Isopropyl GSH (2-BP) S-propyl GSH (1-BP) S-2-hydroxypropyl(oxopropyl) GSH & their mercapturic acid (1,2-DBP) S-2-79/81bromopropenyl GSH (2,3-DBPE) S-3-79/81bromopropyl GSH (1,3-DBP)

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