Download - 2009 약물대사기반 심포지엄-정호상(3)
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Evaluation of Drug Toxicity by Metabolom Profiling
Ho-Sang Jeong, Ph. D
Div. of Pharmacological Research, NIFDS
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protein-gene interactions
protein-protein interactions
PROTEOME
GENOME
Citrate Cycle
METABOLISM
Bio-chemical reactions
From Genes To Metabolites
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Metabolomics: A Multidisciplinary Study
Raw NMR spectraNMR spectra processed PCA
control
disease ortoxicity
STOCSY
UrineSerumtissue
Discovery of biomarkersIdentification of metabolic pathway
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Year Budget (KWon) Contents
2006 32,000
Metabolomics를이용한내분비장애추정물질의안전성 예측 방법 연구(metabolic study of putative endocrine disruptor)
식욕억제제의약물동태 및 대사 연구(Pharmacokinetic study of anorexic drug using metabolomics)
2007 46,000
Metabolomics를이용한 간독성 평가방법 개발 (Liver toxicity study using metabolomics)
NSAIDs 약물의 약물이상반응에 대한 안전성 예측 연구 (1) (ADR study of NSAIDs using metabolomics)
대사체 생체지표를 이용한 내분비계 장애작용 예측 연구(metabolic study of putative endocrine disruptor)
And etc
2008 41,500
Metabolomics를이용한 신독성 평가방법 개발 (Kidney toxicity study using metabolomics)
NSAIDs 약물의 약물이상반응에 대한 안전성 예측 연구 (2) (ADR study of NSAIDs using metabolomics)
And etc
2009 37,000
간독성평가를위한 시험관내시험계에서의전사체대사체 발현 분석 연구(In vitro liver toxicity study using integrated omics technologies)
NSAIDs 약물의 약물이상반응에 대한 안전성 예측 연구 (3)(ADR study of NSAIDs using metabolomics)
And etc.
Total 156,500
Effort of NIFDS for Metabolomic Study
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Metabolomics in Drug Toxicity
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Metabolomic detection of liver and kidney toxicity
-30
-20
-10
0
10
20
30
-70 -60 -50 -40 -30 -20 -10 0 10 20 30 40 50 60 70
t[2]
t[1]
PLS-DA Class 1Class 2
SIMCA-P+ 11 - 13/03/2007 15:45:11
toxicity
control
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Clinical Chemistry
Biomarkers for hepatotoxicity
NMR Spectrometry
Histopathology
Liver damage
D-GalactosamineSD
Hepatotoxicity
Acetaminophen
CCl4
blood
liver
urine
Multi-variate analysis
Study Design: Liver Toxicity
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Treatment and sample collection: Liver Toxicity
CCl4 1 ml/kg, p.o
D-Galactosamine (GalN) 0.8 g/kg, i.p
Acetaminophen (AAP) 2 g/kg, p.o for 2 days
0 1 2
Day
Plasma clinical chemistry (blood)Histopathology (liver)
Urinal NMR (urine)
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Study Design: Kidney Toxicity
Clinical Chemistry
Nephrotoxicity biomarkerMetabolomics
- Urine
Histopathology
Kidney Damage
GentamicinSD
Nephrotoxicity
Cis-platin
HgCl2
Administration HgCl2 0.1 or 0.75 mg/kg, ip
Gentamicin (GEN) 5 or 160 mg/kg for 2 days, ip
Cis-platin (CP) 5 mg/kg for 2 days or 20 mg/kg for single, ip
Kidney weight
p-Aminophenol
p-Aminophenol (PAP) 10 or 200 mg/kg, ip
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Plasma clinical chemistry (blood)Histopathology (kidney)
Days
-1 0 1 2 3 4 5 6
Urinal NMR (urine)
Kidney wtUrinal clinical chemistry (urine)
Treatment
Biomaterial collection for HgCl2 treatment
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Biomaterial collection for PAP treatment
0 1 2
Days
Treatment
3
Plasma clinical chemistry (blood)Histopathology (kidney)
Urinal NMR (urine)
Kidney wtUrinal clinical chemistry (urine)
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Pattern recognition methodsSupervised techniques (PCA)
Unsupervised techniques (PLS-DA)
NMR
Import techniques and procedures in metabonomics
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Control, Day 2 CCl4 1 ml/kg, Day 1 CCl4 1 ml/kg, Day 2
AAP 2 g/kg, Day 2 GalN 0.8 g/kg, Day 1
Con Day
1
Con Day
2 D
ay 1
4CCl D
ay 2
4CCl
Con Day
2
AAP Day
2
Con Day
1
Con Day
2
GalN D
ay 1
GalN D
ay 2
0
2
4
6
8
10
****
**
** **
CCl4 AAP GalNLi
ver
inju
ry s
core
A B C
ED F
Histopathology: Liver
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NMR spectral analysis
1234567ppm
Target profiling Spectral binning
1234567ppm
hippurate urea
allantoincreatininehippurate
2-oxoglutarate
citrate
TMAO
succinatefumaratewater
creatinine
taurine
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SIMCA-P ver.11 (Umetrics, Umeå, Sweden)
Partial Least Squares (PLS) discriminant analysis
Very importance variables (VIP) were also utilized to select putative markers for hepatotoxicity induced by CCl4, AAP, and GalN.
Multivariate statistical data analysis
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Global profiling : Liver Toxicity
CCl4 AAP GalN
■ Day 0● Day 1♦ Day 2
A B C
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Global profiling of hepatotoxicants
Class 1Class 5Class 9Class 11Class 16Class 19
GalN Day 1GalN Day 2CCl4 Day 1CCl4 Day 2AAP Day 2Control (Day 0)
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Targeted profiling of CCl4
CCl4 Day 1CCl4 Day 2Con Day 0Con Day 1Con Day 2
A
B
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Targeted profiling of AAP
AAP Day 1AAP Day 2Con Day 0Con Day 1Con Day 2
A
B
C
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Targeted profiling of GalN
Con Day 0Con Day 1Con Day 2GalN Day 1GalN Day 2
A
B
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2-Oxoglutarate
Con_CCl4_Day 1
CCl4_Day 1
Con_CCl4_Day 2
CCl4_Day 2
Con_AAP_Day 1
AAP_Day 1
Con_GalN_Day 1
GalN_Day 1
Con_GalN_Day 2
GalN_Day 20.0
2.5
5.0
7.5
10.0
**
**
*
Citrate
Con_CCl4_Day 1
CCl4_Day 1
Con_CCl4_Day 2
CCl4_Day 2
Con_AAP_Day 1
AAP_Day 1
Con_GalN_Day 1
GalN_Day 1
Con_GalN_Day 2
GalN_Day 20
1
2
3
4
5
** *
Taurine
Con_CCl4_Day 1
CCl4_Day 1
Con_CCl4_Day 2
CCl4_Day 2
Con_AAP_Day 1
AAP_Day 1
Con_GalN_Day 1
GalN_Day 1
Con_GalN_Day 2
GalN_Day 20
1
2
3
** *** *
Succinate
Con_CCl4_Day 1
CCl4_Day 1
Con_CCl4_Day 2
CCl4_Day 2
Con_AAP_Day 1
AAP_Day 1
Con_GalN_Day 1
GalN_Day 1
Con_GalN_Day 2
GalN_Day 20
1
2
3
4
*
Determination of endogenous metabolites
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Acetate
Con_CCl4_Day 1
CCl4_Day 1
Con_CCl4_Day 2
CCl4_Day 2
Con_AAP_Day 1
AAP_Day 1
Con_GalN_Day 1
GalN_Day 1
Con_GalN_Day 2
GalN_Day 20
5
10
15
20
**
Betaine
Con_CCl4_Day 1
CCl4_Day 1
Con_CCl4_Day 2
CCl4_Day 2
Con_AAP_Day 1
AAP_Day 1
Con_GalN_Day 1
GalN_Day 1
Con_GalN_Day 2
GalN_Day 20.0
0.1
0.2
0.3
Lactate
Con_CCl4_Day 1
CCl4_Day 1
Con_CCl4_Day 2
CCl4_Day 2
Con_AAP_Day 1
AAP_Day 1
Con_GalN_Day 1
GalN_Day 1
Con_GalN_Day 2
GalN_day 20
2
4
6
8
10*
Allantoin
Con_CCl4_Day 1
CCl4_Day 1
Con_CCl4_Day 2
CCl4_Day 2
Con_AAP_Day 1
AAP_Day 1
Con_GalN_Day 1
GalN_Day 1
Con_GalN_Day 2
GalN_Day 20
1
2
3
4
5
**
Determination of endogenous metabolites
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Phenylacetate
Con_CCl4_Day 1
CCl4_Day 1
Con_CCl4_Day 2
CCl4_Day 2
Con_AAP_Day 1
AAP_Day 1
Con_GalN_Day 1
GalN_Day 1
Con_GalN_Day 2
GalN_Day 20.0
0.1
0.2
0.3
0.4
***
1-Methylnicotinamide
Con_CCl4_Day 1
CCl4_Day 1
Con_CCl4_Day 2
CCl4_Day 2
Con_AAP_Day 1
AAP_Day 1
Con_GalN_Day 1
GalN_Day 1
Con_GalN_Day 2
GalN_Day 20.0
0.2
0.4
0.6
*
*
Hippurate
Con_CCl4_Day 1
CCl4_Day 1
Con_CCl4_Day 2
CCl4_Day 2
Con_AAP_Day 1
AAP_Day 1
Con_GalN_Day 1
GalN_Day 1
Con_GalN_Day 2
GalN_Day 20.00
0.05
0.10
0.15
0.20
**
** *
Benzoate
Con_CCl4_Day 1
CCl4_Day 1
Con_CCl4_Day 2
CCl4_Day 2
Con_AAP_Day 1
AAP_Day 1
Con_GalN_Day 1
GalN_Day 1
Con_GalN_Day 2
GalN_4Day 20
1
2
3
**
**
*
Determination of endogenous metabolites
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-3.0 -2.5 -2.0 -1.5 -1.0 -0.5 0.5 1.0 1.5 2.0 2.5 3.0
Standard deviations from mean compound concentration
Compounds
Sam
ples
Hep
atot
oxic
ant
Con
trol
sFingerprint of endogenous metabolites
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Results and conclusion
□ Current study provides that urinary 1H NMR spectral based metabolomics is a new approach to determine the change in endogenous metabolites in animals exposed to hepatotoxicants of CCl4, AAP, and GalN. NMR spectra showed pattern recognition using PLS-DA through distinct separation of clustering in hepatotoxicants-treated urine samples.
This pattern recognition may be used to screen hepatotoxic new drug candidates in early preclinical studies.
We proposed 12 putative biomarkers to predict hepatotoxicity induced by chemicals using NMR targeted analysis.
□ Classical clinical chemistry and histopathology provided validation for this study and this database of biomarker patterns may be useful for further study.
□ The suggested biomarkers should be explained how to involve in mechanism of hepatic injury. The further study with other hepatotoxicants needs to identify the endogenous biomarkers.
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Histopathology : Kidney-HgCl2
×100
Control
HgCl2_0.75 mg/kg_D6
HgCl2_0.1 mg/kg_D6
HgCl2_0.75 mg/kg_D3
HgCl2_0.1 mg/kg_D3a b c
d e
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Global Profiling (PCA): HgCl2
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Global Profiling (PLS-DA): HgCl2
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Targeted Profiling (PCA): HgCl2
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Targeted Profiling (PLS-DA): HgCl2
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Targeted Profiling (PLS-DA): HgCl2
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Summary- HgCl2
Global profiling- clustering of samples by HgCl2 treatment - clear temporal profiling by HgCl2 administration
Target Profiling- similar to Global profiling- endogenous metabolites related to HgCl2 caused kindey toxicity: Glucose, acetate, allantoin, 2-oxoglutarate, alanine, lactate, formate, citrate, succinate, taurine, ethanol, hippurate
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Histopathology : Kidney-Cisplatin
Control Cisplatin_5 mg/kg_D8
Cisplatin_20 mg/kg_D2
Cisplatin_5 mg/kg_D2
Cisplatin_20 mg/kg_D8
a
ed
cb
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Global Profiling (PCA) : Cisplatin
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Global Profiling (PLS-DA) : Cisplatin
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Targeted Profiling (PLS-DA) : Cisplatin
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Targeted Profiling (PLS-DA) : Cisplatin
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Summary-Cisplatin
Global profiling - Clustering of samples by Cisplatin- Clear temporal profiling by Cisplatin
Target Profiling_PLS-CA- similar to global profiling- endogenous metabolites related to cisplatine caused kidney toxicity: N-acetylglycine, cinnamate, dimethylamine, hippurate, niacinamide, 2-oxoglutarate, lactate, cis-aconitine, 3-indoxylate, propionate, nicotinate, creatine, acetate, ethanol, phenylacetate
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Histopathology : Kidney-Gentamicin
Control Gentamicin_5 mg/kg_D8
Gentamicin_160 mg/kg_D2
Gentamicin_5 mg/kg_D2
Gentamicin_160 mg/kg_D8
a
ed
cb
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Global Profiling (PCA) : Gentamicin
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Global Profiling (PLS-DA) : Gentamicin
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Targeted Profiling (PLS-DA) : Gentamicin
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Targeted Profiling (PLS-DA) : Gentamicin
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Summary-Gentamicin
Global profiling - Clustering of samples by gentamicin- Clear temporal profiling by gentamicin
Target Profiling_PLS-DA- Similar to global profiling- Endogenous metabolites related to cisplatine caused kidney toxicity: Acetate, 2-oxoglutarate, glucose, allantoin, lactate, formate, citrate, glycine, taurine, benzoate, succinate, alanine
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Histopathology : Kidney-p-Aminophenol
Control PAP_10 mg/kg_D3
PAP_200 mg/kg_D1
PAP_10 mg/kg_D1
PAP_200 mg/kg_D3
a
ed
cb
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Global Profiling (PCA) : p-Aminophenol
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Global Profiling (PLS-DA) : p-Aminophenol
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Targeted Profiling (PCA) : p-Aminophenol
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Targeted Profiling (PLS-DA) : p-Aminophenol
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Targeted Profiling (PLS-DA) : p-Aminophenol
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Summary: p-Aminophenol
Global profiling - clustering of smaples by p-aminophenol- Stable temporal profiling by p-aminophenol
Target Profiling_PLS-DA- Similar to global profiling- Endogenous metabolites related to p-aminophenolcaused kidney toxicity: Glucose, lactate, alanine, 2-oxoglutarate, acetate, allantoin, citrate, formate, taurine, creatine, succinate
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Common Metabolic Markers
HgCl2Cisplatin
Gentamicin p-Aminophenol
glucoseacetateallantoin
2-oxoglutaratealanine
lactate
formate
citrate
succinate
taurine
ethanol
hippurate
N-acetylglycinecinnamate
dimethylamineniacinamide
Cis-aconitine3-indoxylate
propionatenicotinate
creatine
phenylacetate
glycine
benzoate
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Determination of endogenous metabolites (2-oxoglutarate)
HgCl2
D0 D2 D3 D4 D5 D6 D0 D2 D3 D4 D5 D60
2
4
6
8
10Hg_0.1Hg_0.75
**
Days after treatment
2-O
xogl
utar
ate
Cisplatin
D0 D2 D3 D4 D5 D6 D7 D8 D0 D2 D3 D4 D5 D6 D7 D80
1
2
3
4
5CP_20CP_5
***
**
**
** ** ** ** **
Days after treatment
2-O
xogl
utar
ate
Gentamicin
D0 D2 D3 D4 D5 D6 D7 D8 D0 D2 D3 D4 D5 D6 D7 D80
2
4
6GEN_5GEN_160
*
** ** ** ** **
Days after treatment
2-O
xogl
utar
ate
p-Aminophenol
D0 D2 D3 D0 D2 D30
1
2
3PAP_10PAP_200
**
**
**
Days after treatment
2-O
xogl
utar
ate
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Determination of endogenous metabolites (Taurine)
HgCl2
D0 D2 D3 D4 D5 D6 D0 D2 D3 D4 D5 D60.0
0.5
1.0
1.5Hg_0.1Hg_0.75
**
**** ** **
Days after treatment
Taur
ine
Cisplatin
D0 D2 D3 D4 D5 D6 D7 D8 D0 D2 D3 D4 D5 D6 D7 D80
1
2
3
4
5CP_20CP_5
**
Days after treatment
Taur
ine
Gentamicin
D0 D2 D3 D4 D5 D6 D7 D8 D0 D2 D3 D4 D5 D6 D7 D80.0
0.5
1.0
1.5
2.0
2.5GEN_5GEN_160
Days after treatment
Taur
ine
p-Aminophenol
D0 D2 D3 D0 D2 D30.0
0.5
1.0
1.5PAP_10PAP_200
**
Days after treatment
Taur
ine
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-3.0 -2.5 -2.0 -1.5 -1.0 -0.5 0.5 1.0 1.5 2.0 2.5 3.0
Standard deviations from mean compound concentrationEn
doge
nous
met
abol
ites
NephrotoxicantsControl
Fingerprint of endogenous metabolites
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Metabolic markers for Nephrotoxicity and Hepatotoxicity
Biomarkers Nephrotoxicity(2008)
Hepatotoxicity(2007)
acetatelactate
alanine
allantoincitrate
2-oxoglutarate
glucose -formate -
taurine
succinatephenylacethyl glycine -
1-methylnicotinamide -
hippurate -
benzoate -phenylacetate -