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

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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)

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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)

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Structural biology

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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)