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Molecular and cellular mechanisms of phototoxicity. Multidisciplinary strategy for predicting in vitro the phototoxic risk of new drugs to humans

Objective

- Identification of the mechanistic routes and the reactive species (radicals, singlet oxygen, etc.) involved in drug photosensitisation and development of specific mechanistic assays.
- lmprovement of the sensitivity and prediction accuracy of in vitro phototoxicity models: end-points for the early detection of cell misfunction (inflammatory mediators, heat-shock proteins);.
- Assessment of systemic drug phototoxicity
- Elucidation of the basic mechanisms of drug photoallergy.
- lnvestigation of the mechanisms of drug-photosensitised genotoxicity, mutagenicity and carcinogenesis
- Analysis of in vitro results on the basis of human in vivo data (prospective and/or retrospective clinical studies on drug photosensitisation).
- Establishment of structure-activity relationships.

There is accumulated evidence that the interaction of drugs with sunlight may result in cutaneous phototoxicity. Its prediction has been attempted using both in vivo and in vitro models. Although some advances have been achieved, the results are frequently misleading because they presently provide limited mechanistic information. Phototoxicity starts with sunlight absorption by the drug, which reaches an excited state. This species often deactivates through the formation of free radicals or sing let oxygen, which are able to promote oxidation of biomolecules. Further possibilities are the formation of toxic photoproducts or photobinding to biomolecules. Any of the above routes may trigger adversecutaneous effects. In view of the mechanistic complexity, research is needed to develop reliable models to anticipate the phototoxic risk of new drugs to human health. In order to design such methodologies some aspects demand further attention, e.g. relationship between photochemical mechanisms involved and observed cellular effects, potential phototoxicity of drug metabolites and/or toxicity of photoproducts to inner organs, mechanism of photosensitised DNA damage and its consequences (photogenotoxicity, photomutagenicity and phototumourigenesis), elucidation of the critical steps in the onset of photoallergy, identification of the potentially active chromophores and establishment of quantitative structure-activity relationships.

The aim of this project is to gain a better understanding of the molecular and cellular mechanisms of drug phototoxicity, in order to better predict the phototoxicity risk of new active molecules prior to their clinical use.

This will require reaching the following precise objectives:
a) identification of the mechanistic routes and the reactive species (radicals, singlet oxygen) involved in drug photosensitisation and development of specific mechanistic assays;
b) improvement of the sensitivity and prediction accuracy of in vitro models: end-points for the early detection of cell misfunction(inflammatory mediators, heatshock proteins);
c) assessment of systemic phototoxicity;
d) elucidation of the basic mechanisms of drug photoallergy;
e)analysis of in vitro results on the basis of human in vivo data (prospective and/or retrospective clinical studies) and;
f) establishment of structure-activity relationships in the photosensitisation by drugs.

Accomplishment of the above objectives is expected to lead to a more accurate and predictive second generation of in vitro phototoxicity tests.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

Hospital Universitario de la Fe 'Sevasa'
Address
21,Avenida Campanar
46009 Valencia
Spain

Participants (9)

Bayer AG
Germany
Address
Aprather Weg
42096 Wuppertal
Institut National de la Santé et de la Recherche Médicale
France
Address
Avenue Claude Vellefaux
75475 Paris
L'Oréal SA
France
Address
1,Avenue Eugène Schueller
93601 Aulnay-sous-bois
LEIDEN UNIVERSITY
Netherlands
Address
55,Einsteinweg 55 Gorlaeus Laboratories
2333 CC Leiden
Muséum National d'Histoire Naturelle
France
Address
43,Rue Cuvier
75231 Paris
UNIVERSIDAD POLITECNICA DE VALENCIA
Spain
Address
S/n,avenida De Los Naranjos S/n
46022 Valencia
UNIVERSITY OF MANCHESTER
United Kingdom
Address
Oxford Road
M13 9PL Manchester
Unilever UK Central Resources Ltd
United Kingdom
Address
Colworth House
MK44 1LQ Bedford
University of Dundee
United Kingdom
Address
Ninewells Hospital And Medical School
DD1 9SY Dundee