Cellular photo(geno)toxicity of gefitinib after biotransformation

Meryem El Ouardi; Lorena Tamarit; Ignacio Vayá; Miguel A Miranda; Inmaculada Andreu

doi:10.3389/fphar.2023.1208075

Cellular photo(geno)toxicity of gefitinib after biotransformation

Front Pharmacol. 2023 Jun 7:14:1208075. doi: 10.3389/fphar.2023.1208075. eCollection 2023.

Authors

Meryem El Ouardi^{1

2}, Lorena Tamarit^{1

2}, Ignacio Vayá^{1

2}, Miguel A Miranda^{1

2}, Inmaculada Andreu^{1

2}

Affiliations

¹ Departamento de Química-Instituto de Tecnología Química UPV-CSIC, Universitat Politècnica de València, Valencia, Spain.
² Unidad Mixta de Investigación UPV- IIS La Fe, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Abstract

Gefitinib (GFT) is a selective epidermal growth factor receptor (EGFR) inhibitor clinically used for the treatment of patients with non-small cell lung cancer. Bioactivation by mainly Phase I hepatic metabolism leads to chemically reactive metabolites such as O-Demethyl gefitinib (DMT-GFT), 4-Defluoro-4-hydroxy gefitinib (DF-GFT), and O-Demorpholinopropyl gefitinib (DMOR-GFT), which display an enhanced UV-light absorption. In this context, the aim of the present study is to investigate the capability of gefitinib metabolites to induce photosensitivity disorders and to elucidate the involved mechanisms. According to the neutral red uptake (NRU) phototoxicity test, only DF-GFT metabolite can be considered non-phototoxic to cells with a photoirritation factor (PIF) close to 1. Moreover, DMOR-GFT is markedly more phototoxic than the parent drug (PIF = 48), whereas DMT-GFT is much less phototoxic (PIF = 7). Using the thiobarbituric acid reactive substances (TBARS) method as an indicator of lipid photoperoxidation, only DMOR-GFT has demonstrated the ability to photosensitize this process, resulting in a significant amount of TBARS (similar to ketoprofen, which was used as the positive control). Protein photooxidation monitored by 2,4-dinitrophenylhydrazine (DNPH) derivatization method is mainly mediated by GFT and, to a lesser extent, by DMOR-GFT; in contrast, protein oxidation associated with DMT-GFT is nearly negligible. Interestingly, the damage to cellular DNA as revealed by the comet assay, indicates that DMT-GFT has the highest photogenotoxic potential; moreover, the DNA damage induced by this metabolite is hardly repaired by the cells after a time recovery of 18 h. This could ultimately result in mutagenic and carcinogenic effects. These results could aid oncologists when prescribing TKIs to cancer patients and, thus, establish the conditions of use and recommend photoprotection guidelines.

Keywords: anticancer drug; metabolism; photodamage to biomolecules; photosensitized reaction; tyrosine kinase inhibitor.

Grants and funding

This research was funded by the MICINN (Grant PID2020-115010RB-I00 funded by MCIN/AEI/10.13039/501100011033, RYC-2015-17737 and FPU predoctoral fellowship for ME.).