Photo(geno)toxicity changes associated with hydroxylation of the aromatic chromophores during diclofenac metabolism

Autores de IIS La Fe

• Guillermo Garcia Lainez

  Autor

• María Consuelo Jiménez Molero

  Autor

• Miguel Ángel Miranda Alonso

  Autor

• Inmaculada Andreu Ros

  Autor

Participantes ajenos a IIS La Fe

• Martinez-Reig, AM
• Limones-Herrero, D

Grupos

• Unidad Mixta de Investigación en Mecanismos moleculares de las Reacciones adversas de fármacos

Abstract

Diclofenac (DCF) can cause adverse reactions such as gastrointestinal, renal and cardiovascular disorders; therefore, topical administration may be an attractive alternative to the management of local pain in order to avoid these side effects. However, previous studies have shown that DCF, in combination with sunlight, displays capability to induce photosensitivity disorders. In humans, DCF is biotransformed into hydroxylated metabolites at positions 4' and 5 (4'OH-DCF and 5OH-DCF), and this chemical change produces non negligible alterations of the drug chromophore, resulting in a significant modification of its light-absorbing properties. In the present work, 5OH-DCF exhibited higher photo(geno)toxic potential than the parent drug, as shown by several in vitro assays (3T3 NRU phototoxicity, DNA ssb gel electrophoresis and COMET), whereas 4'OH-DCF did not display significant photo(geno)toxicity. This could be associated, at least partially with their more efficient UV-light absorption by 5OH-DCF metabolite and with a higher photoreactivity. Interestingly, most of the cellular DNA damage photosensitized by DCF and 5OH-DCF was repaired by the cells after several hours, although this effect was not complete in the case of 5OH-DCF.

Keywords

• Comet assay; DNA repair capability; Metabolites; Photosensitized DNA damage; Phototoxicity