Transcript Xenobiotic - L`Université Paris Descartes

1ère Journée de Biologie Systémique
Université Paris 5
La Biologie des Systèmes en Toxicologie
Robert Barouki
UMR-S 747 INSERM Université Paris 5
Pharmacologie Toxicologie et Signalisation Cellulaire
Centre des Saints Pères
22 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
Environmental Toxicology: a global system
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Environmental Toxicology: a global system
exposure
External
contact
Internal
dose
sources
contaminants
Internal
contamination
Preclinical
response
biomarkers
New technologies
Can we predict toxicity?
Clinical
response
Drug Toxicity: the organism as a system
Target tissues
Toxicity
Drug Toxicity:
Impact de a
la health
toxicitéand
des economical
médicamentsissue
Can we predict toxicity?
Paradise on earth low cost, high efficiency
Predictive and Mechanistic Toxicology
Can New Technologies help?
 High
throughput technologies: the « omics »
Lessons from molecular and cellular biology
Analytical Methods
Systems biology
In silico prediction
Invasion of Toxicology by the OMICS
physiome
Metabonomics
Metabolomics
Proteomics
metabolome
proteome
Functional
genomics
transcriptome
Just add Toxico-
genome
Structural genomics
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
The number of genes (1)
20 000 genes
The Worm C elegans
25 000 genes
The most powerful
man in the world
Not Surprised??
The number of genes (2)
20 000 genes
The Worm C elegans
25 000 genes
René Descartes
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
The Xenobiotics Stress System
Xenobiotics are low molecular weight foreign
Substances:
Drugs
Pollutants
Nutrients
Similar responses at the cellular level
Exposure to xenobiotics is accompanied by a stress
What is a stress??
Stress: the word
Physics: response of a metal
Physiology: a defined set of responses to
extreme situations (Selye)
Cell biology: response of a cell to aggression
Psychology-social sciences: response of an
individual or of a group
Stress is an adaptive response to a significant
shift in cellular conditions
This response has a cost
Xenobiotics stress
Xenobiotics
Receptor:
Detection and induction
O-Conj
Enzymes (XMEs) and transporteurs:
Metabolism and exits
elimination
Adaptation:
1- detection of xenobiotics and gene induction
2- transformation and elimination
Metabolism of Xenobiotics
the Detoxication System
Xenobiotic
MDR
Receptor
CYP
Phase I
OH
GST UGT
Phase II
O-Conj
MRP
Phase III
O-Conj
Legitimate and Illegitimate Receptors for Xenobiotics
Multiple Pathways and Dangerous Liaisons
steroid hormones
ER
AhR
Xenobiotics
lipids
PXR - CAR
PPAR
Xenobiotics receptors
Endocrine
disruption
Adaptation
and stress
possible toxicity
Metabolic
disruption
Both legitimate and illegitimate liaisons
can be dangerous
Dioxin
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Cl
O
Cl
Cl
O
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??
The Dioxin Receptor System:
lessons from genomics
Hundreds maybe Thousands of ligands: xeno or endo
Cell cycle
Xenobiotics
metabolism
Cell
migration
Lipid
metabolism
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
Rb
Src
NFkB
inflammation
ARNT
proliferation
HIF
hypoxia
Few large scale studies. Use of Protein interaction network in yeast
Yao et al, PLOS Biology, 2004
The Dioxin Receptor System:
lessons from metabolism
CYP
BP
OH
BP
DNA adduct
genotoxicity
H2O2
p53
Oxidative stress
The p53 system
apoptosis
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 European
Bioinformatics 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)
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Structural biology
The promiscuity of the
PXR
revealed by its structure:
3 possible positions for a
single molecule
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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 networks
protein interaction networks
Metabolic 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)