1re Journe de Biologie Systmique Universit Paris 5

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 üDrug and polluants toxicity: differences and similarities üGlobal systems üThe Organism as a system üCellular and molecular systems

Environmental Toxicology: a global system

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? ü High throughput technologies: the « omics » üLessons from molecular and cellular biology üAnalytical Methods üSystems biology üIn 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? ? üLarge scale detection of polymorphisms, in particular SNPs üA fraction of toxicity can be explained by gene structure üIndividual susceptibility üPharmaco- 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? ü gene regulation (toxicogenomics) ü m. RNA splicing (toxicogenomics) ü m. RNA degradation (toxicogenomics) ü Protein stability (toxicoproteomics) ü Post translational regulation (toxicoproteomics) ü Protein-protein interaction (interactomes) ü connection of metabolic parthways (metabolomics) ü Systems biology: a comprehensive description

The Xenobiotics Stress System Xenobiotics are low molecular weight foreign Substances: üDrugs üPollutants üNutrients Similar responses at the cellular level Exposure to xenobiotics is accompanied by a stress

What is a stress? ? Stress: the word üPhysics: response of a metal üPhysiology: a defined set of responses to extreme situations (Selye) üCell biology: response of a cell to aggression üPsychology-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 Ah. R 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 Cl O Cl Tetra. Chloro. Dibenzo. Dioxin: TCDD - Lessons from the chemistry - Receptor: Ah. R, shared with other pollutants, xenobiotics and endogenous compounds - Induction of XMEs (CYP 1 A 1): 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 NFk. B 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 H 2 O 2 p 53 Oxidative stress The p 53 system apoptosis Large scale studies: predictive pharmaco-metabonomic phenotyping using urinary samples (Clayton et al, Nature, 2006)

Consortia and databases in Toxicogenomics üILSI Health and Environmental Service Institute (collab European Bioinformatics Institute) üToxicogenomics Research Consortium (National Center for Toxicogenomics) üCOMET: Consortium for Metabonomics Technology üEDGE: Environment, Drugs and Gene Expression üPharm. GKB: Pharmaco. Genomics Knowledge Base ü CEBS: Chemical Effect in Biological Systems Knowledge Base üProtein Interaction Network

Structural biology Major breakthroughs in drug metabolism (CYP 3 A 4) and drug inductioin (PXR)

Structural biology The promiscuity of the PXR revealed by its structure: 3 possible positions for a single 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 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 üMolecular and global aspects: integrates systems biology as well as more traditional toxicological data üDescribes new mechanisms üHigh Predictive power: development of safer drugs and safer chemicals (Reach protocol of the EU)