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Drug hepatotoxicity: an integrated clinical and mechanistic investigation

Objective

The general aim is to detect, understand, predict and avoid drug hepatotoxicity:
Clinical studies will be undertaken to elucidate clinical, environmental and pharmacogenetic risk factors and to determine whether modulation of drug bioactivation/detoxication in patients in vivo influences their susceptibility
Mechanistic investigations will be used to investigate pathways of drug bioactivation and toxicity, and to define cellular and immunoallergic mechanisms of drug toxicity.

Drug hepatotoxicity is a major clinical and socio-economic problem in the E.C. This is because hepatotoxicity is among the most frequent of the organ toxicities caused by drugs and because drug-induced hepatotoxicity may lead to chronic disease, death or liver transplantation. Although hundreds of hepatotoxic drugs have now been identified, in only a few cases have the mechanisms of toxicity been defined. In consequence, little is known concerning the reasons why some patients are susceptible to the hepatotoxicities, but many other patients are not. Furthermore, model systems which can be used to predict and study the toxicities are not available. In view of this, a multidisciplinary and multinational European research network (EUROHEPATOX) will be established and a strategy will be adopted which will make possible integrated clinical, molecular and cellular studies of mechanisms of drug hepatotoxicity.
Clinical studies:
Detection of patients with drug hepatotoxicity via prospective/retrospective trials
Investigation of clinical, environmental and pharmacogenetic risk factors
effects of modulating bioactivation/bioinactivation on patients' susceptibility
Drug bioactivation and bioinactivation
Identification of metabolic and genetic risk factors and chemoprotective factors
Development and validation of novel in vitro techniques
Cellular mechanisms of drug hepatotoxicity
Apoptosis, mitochondrial toxicity, oxidative stress
Interrelationships with metabolic and genetic factors affecting bioactivation
Immunoallergic mechanisms of drug hepatotoxicity
Identification and characterization of hepatic protein adducts
Interrelationships between adduct expression and drug bioactivation
Antibody and T cell response to the adducts in patients
In vitro models of immunoallergic drug hepatotoxicity.
This general strategy will be used to investigate four groups of themed drugs, which have been chosen for study because they are important and widely prescribed and because the toxicities observed in patients treated with these drugs differ markedly with respect to incidence and patterns of liver injury. These are the nonsteroidal antiinflammatory drugs (NSAIDs), penicillins, tacrine (which recently has been introduced for treatment of Alzheimer's disease) and the anti-cancer drugs. The objective is to develop techniques and approaches (particularly in vitro methodologies) which will make possible: safer and more effective use of existing drugs
development and evaluation of new and less toxic drugs.

Coordinator

Imperial College of Science Technology and Medicine
Address
Norfolk Place
W2 1PG London
United Kingdom

Participants (18)

Centre Hospitalier Universitaire de Rouen
France
Address
1,Rue De Germont
76031 Rouen
Centre Hospitalier Universitaire de Toulouse
France
Address
37,Allée Jules-guesde
31073 Toulouse
Eidgenössische Technische Hochschule - ETH Zürich
Switzerland
Address
16,Schorenstrasse
8603 Zürich
Erasmus Universiteit Rotterdam
Netherlands
Address
50,Dr Molewaterplein
3000 RN Rotterdam
Hospital Universitario de la Fe 'Sevasa'
Spain
Address
21,Avenida Campanar
46009 Valencia
Institut National de la Santé et de la Recherche Médicale
France
Address
156,Rue De Vaugirard
75730 Paris
Institut National de la Santé et de la Recherche Médicale
France
Address
27,Rue Chaligny
75571 Paris
Institut National de la Santé et de la Recherche Médicale (INSERM)
France
Address
100 Boulevard Du Général Leclerc
92118 Clichy
Istituto di Ricerche Farmacologiche Mario Negri
Italy
Address
Via Eritrea 62
20157 Milano
KAROLINSKA INSTITUTE
Sweden
Address
9,Doktorsringen 9 A
171 77 Stockholm
National University of Ireland, Cork
Ireland
Address

30 Cork
Odense Universitet
Denmark
Address
19,Winslowparken
5000 Odense C
Robert-Bosch-Krankenhaus GmbH
Germany
Address
110,Auerbachstrasse
70376 Stuttgart
Universidade de Lisboa
Portugal
Address
Av. Professor Egas Moniz
1699 Lisboa
University of Newcastle Upon Tyne
United Kingdom
Address
Framlington Place
NE2 4HH Newcastle - Upon Tyne
Université Pierre et Marie Curie - Paris VI
France
Address
184,Rue Du Faubourg Saint-antoine
75571 Paris
Université de Rennes I
France
Address
Chru Pontchaillou
35033 Rennes
VRIJE UNIVERSITEIT AMSTERDAM - VERENIGING VOOR CHRISTELIJK WETENSCHAPPELIJK ONDERWIJS
Netherlands
Address
1083,De Boelelaan 1083
1081 HV Amsterdam