Diapositive 1

1
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
2
A variety of Systems in Toxicology

• Drug and polluants toxicity differences and
  similarities
• Global systems
• The Organism as a system
• Cellular and molecular systems

3
Environmental Toxicology a global system
4
Environmental Toxicology a global system
Clinical response
Preclinical response
Internal dose
External contact
exposure
contaminants
Internal contamination
biomarkers
sources
New technologies
Can we predict toxicity?
5
Drug Toxicity the organism as a system
Target tissues
Toxicity
6
Drug Toxicity a health and economical issue
Impact de la toxicité des médicaments
Can we predict toxicity?
7
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

8
Invasion of Toxicology by the OMICS
Metabonomics Metabolomics
Functional genomics
Proteomics
Structural genomics
Just add Toxico-
9
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

10
Not Surprised??
11
The number of genes (2)
25 000 genes René Descartes
20 000 genes The Worm C elegans
Complexity is not only related to the number of
genes
12
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

13
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
14
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
15
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
16
Metabolism of Xenobiotics the Detoxication System
17
Legitimate and Illegitimate Receptors for
Xenobiotics Multiple Pathways and Dangerous
Liaisons
Xenobiotics
lipids
steroid hormones
PPAR
ER
Endocrine disruption
Adaptation and stress possible toxicity
Metabolic disruption
Both legitimate and illegitimate liaisons can be
dangerous
18
Dioxin
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??

19
The Dioxin Receptor System lessons from genomics
Hundreds maybe Thousands of ligands xeno or endo
Lipid metabolism
Cell cycle
Xenobiotics metabolism
Cell migration
Large number of toxicogenomics studies Marchand
et al, Mol Pharmacol, 2005
20
TCDD Cell Morphology and Motility
Diry et al, Oncogene, 2006,
21
The Dioxin Receptor System lessons from protein
interaction
Rb Src
NFkB
inflammation
proliferation
ARNT
HIF
hypoxia
Few large scale studies. Use of Protein
interaction network in yeast Yao et al, PLOS
Biology, 2004
22
The Dioxin Receptor System lessons from
metabolism
CYP
OH
DNA adduct genotoxicity
BP
BP
H2O2
p53
Oxidative stress
The p53 system apoptosis
Large scale studies predictive
pharmaco-metabonomic phenotyping using urinary
samples (Clayton et al, Nature, 2006)
23
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

24
Structural biology
Major breakthroughs in drug metabolism (CYP3A4)
and drug inductioin (PXR)
25
Structural biology
The promiscuity of the PXR revealed by its
structure 3 possible positions for a single
molecule
26
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
27
Iterative modelling for drug development
integrating ADMET
28
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.
29
A Systems Biology Approach the case of
4-OH-tamoxifen
Metadrug (http/www.genego.com)
30
Toxicology Systems Biology a global approach
31
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)