View
215
Download
2
Category
Preview:
Citation preview
1ère Journée de Biologie SystémiqueUniversité Paris 5
La Biologie des Systèmes en Toxicologie
Robert BaroukiUMR-S 747 INSERM Université Paris 5
Pharmacologie Toxicologie et Signalisation Cellulaire
Centre des Saints Pères22 Mai 2006
A variety of Systems in Toxicology
Drug and polluants toxicity: differences and similarities
Global systems
The Organism as a system
Cellular and molecular systems
QuickTime™ et undécompresseur TIFF (LZW)
sont requis pour visionner cette image.
Environmental Toxicology: a global system
Clinicalresponse
Preclinicalresponse
contaminantsInternal
contaminationbiomarkers
New technologies
Internal dose
External contact
exposure
Environmental Toxicology: a global system
sources
Can we predict toxicity?
Drug Toxicity: the organism as a system
Target tissues
Toxicity
Impact de la toxicité des médicamentsDrug Toxicity: a health and economical issue
Can we predict toxicity?
High throughput technologies: the « omics »
Lessons from molecular and cellular biology
Analytical Methods
Systems biology
In silico prediction
Paradise on earth low cost, high efficiency Predictive and Mechanistic Toxicology
Can New Technologies help?
Invasion of Toxicology by the OMICS
Structural genomics
Functional genomics
genome
transcriptome
proteome
metabolome
physiome
Proteomics
MetabonomicsMetabolomics
Just add Toxico-
Is it all in the gene structure??
Large scale detection of polymorphisms, in particular SNPs
A fraction of toxicity can be explained by gene structure
Individual susceptibility
Pharmaco- and Toxico-genetics
25 000 genesThe most powerfulman in the world
Not Surprised??
20 000 genesThe Worm C elegans
The number of genes (1)
20 000 genesThe Worm C elegans
25 000 genesRené Descartes
The number of genes (2)
Complexity is not only related to the number of genes
Where does complexity come from?
gene regulation (toxicogenomics) mRNA splicing (toxicogenomics) mRNA degradation (toxicogenomics) Protein stability (toxicoproteomics) Post translational regulation (toxicoproteomics) Protein-protein interaction (interactomes) connection of metabolic parthways (metabolomics) Systems biology: a comprehensive description
Xenobiotics are low molecular weight foreign Substances:
DrugsPollutantsNutrients
Similar responses at the cellular level
Exposure to xenobiotics is accompanied by a stress
The Xenobiotics Stress System
What is a stress??
Stress: the wordPhysics: response of a metalPhysiology: a defined set of responses to extreme situations (Selye)Cell biology: response of a cell to aggressionPsychology-social sciences: response of an individual or of a group
Stress is an adaptive response to a significantshift in cellular conditionsThis response has a cost
Stress is an adaptive response to a significantshift in cellular conditionsThis response has a cost
Xenobiotics stress
Xenobiotics
Enzymes (XMEs) and transporteurs:Metabolism and exits
O-Conj
Receptor:Detection and induction
elimination
Adaptation:1- detection of xenobiotics and gene induction2- transformation and elimination
Adaptation:1- detection of xenobiotics and gene induction2- transformation and elimination
Metabolism of Xenobiotics the Detoxication System
Xenobiotic
OH
Phase I
CYP
Phase II Phase III
O-ConjO-ConjGST UGTMDR MRP
Receptor
Legitimate and Illegitimate Receptors for XenobioticsMultiple Pathways and Dangerous Liaisons
PPAR
Xenobiotics
Endocrine disruption
ER
lipidssteroid hormones
Adaptation and stress
possible toxicity
Metabolic disruption
Both legitimate and illegitimate liaisons can be dangerous
AhR PXR - CAR Xenobiotics receptors
O
O
Cl
Cl
Cl
Cl
TetraChloroDibenzoDioxin: TCDD
- Lessons from the chemistry- Receptor: AhR, shared with other pollutants, xenobiotics and endogenous compounds- Induction of XMEs (CYP1A1): adaptation and stress response- Regulation of dozens of other genes: What for??
Dioxin QuickTime™ et undécompresseur TIFF (LZW)
sont requis pour visionner cette image.
The Dioxin Receptor System: lessons from genomics
Xenobiotics metabolism
Hundreds maybe Thousands of ligands: xeno or endo
Cell cycleCell
migration
Lipidmetabolism
Large number of toxicogenomics studies; Marchand et al, Mol Pharmacol, 2005
TCDD Cell Morphology and Motility
Diry et al, Oncogene, 2006,
The Dioxin Receptor System: lessons from protein interaction
ARNT
NFkB RbSrc
HIF
inflammation
hypoxia
proliferation
Few large scale studies. Use of Protein interaction network in yeastYao et al, PLOS Biology, 2004
The Dioxin Receptor System: lessons from metabolism
BP
OHCYPBP
DNA adductgenotoxicity
p53
The p53 systemapoptosis
H2O2
Oxidative stress
Large scale studies: predictive pharmaco-metabonomic phenotyping using urinary samples (Clayton et al, Nature, 2006)
Consortia and databases in Toxicogenomics
ILSI Health and Environmental Service Institute (collab EuropeanBioinformatics Institute)
Toxicogenomics Research Consortium (National Center for Toxicogenomics)
COMET: Consortium for Metabonomics Technology
EDGE: Environment, Drugs and Gene Expression
PharmGKB: PharmacoGenomics Knowledge Base
CEBS: Chemical Effect in Biological Systems Knowledge Base
Protein Interaction Network
Structural biology
Major breakthroughs in drug metabolism (CYP3A4) and drug inductioin (PXR)
QuickTime™ et undécompresseur TIFF (non compressé)
sont requis pour visionner cette image.
Structural biology
QuickTime™ et undécompresseur TIFF (non compressé)
sont requis pour visionner cette image.
The promiscuity of the PXRrevealed by its structure:3 possible positions for asingle molecule
In silico prediction
Mosly developped for ADMET:Absorption, Distribution, Metabolism, excretion, Toxicity
Data modelling: QSAR (Quantitative Structure Activity Relationship).Correlate a set of molecular or structural descriptors of a drug with a defined property (such a particular toxicity)Highly dependent on the quality of the data and the mathematical approach
Molecular modelling: mostly based on structural information and modelling to predict ligand protein interaction
Iterative modelling for drug development integrating ADMET
A Systems Biology Approach
Goal: build a model integrating all data:genomics, protein interaction, metabolic pathway,
toxicity…
Be as quantitative as possible
Predict the consequences of perturbation in the system
Can be more focused: gene regulation networksprotein interaction networksMetabolic pathways….
A Systems Biology Approach: the case of 4-OH-tamoxifen
Metadrug (http:/www.genego.com)
Toxicology Systems Biology: a global approach
Systems Toxicology
Molecular and global aspects: integrates systems biology as well as more traditional toxicological data
Describes new mechanisms
High Predictive power: development of safer drugs and safer chemicals (Reach protocol of the EU)
Recommended