PMID- 37351506
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230701
IS  - 1663-9812 (Print)
IS  - 1663-9812 (Electronic)
IS  - 1663-9812 (Linking)
VI  - 14
DP  - 2023
TI  - Cellular photo(geno)toxicity of gefitinib after biotransformation.
PG  - 1208075
LID - 10.3389/fphar.2023.1208075 [doi]
LID - 1208075
AB  - 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.
CI  - Copyright (c) 2023 El Ouardi, Tamarit, Vaya, Miranda and Andreu.
FAU - El Ouardi, Meryem
AU  - El Ouardi M
AD  - Departamento de Quimica-Instituto de Tecnologia Quimica UPV-CSIC, Universitat 
      Politecnica de Valencia, Valencia, Spain.
AD  - Unidad Mixta de Investigacion UPV- IIS La Fe, Hospital Universitari i Politecnic 
      La Fe, Valencia, Spain.
FAU - Tamarit, Lorena
AU  - Tamarit L
AD  - Departamento de Quimica-Instituto de Tecnologia Quimica UPV-CSIC, Universitat 
      Politecnica de Valencia, Valencia, Spain.
AD  - Unidad Mixta de Investigacion UPV- IIS La Fe, Hospital Universitari i Politecnic 
      La Fe, Valencia, Spain.
FAU - Vaya, Ignacio
AU  - Vaya I
AD  - Departamento de Quimica-Instituto de Tecnologia Quimica UPV-CSIC, Universitat 
      Politecnica de Valencia, Valencia, Spain.
AD  - Unidad Mixta de Investigacion UPV- IIS La Fe, Hospital Universitari i Politecnic 
      La Fe, Valencia, Spain.
FAU - Miranda, Miguel A
AU  - Miranda MA
AD  - Departamento de Quimica-Instituto de Tecnologia Quimica UPV-CSIC, Universitat 
      Politecnica de Valencia, Valencia, Spain.
AD  - Unidad Mixta de Investigacion UPV- IIS La Fe, Hospital Universitari i Politecnic 
      La Fe, Valencia, Spain.
FAU - Andreu, Inmaculada
AU  - Andreu I
AD  - Departamento de Quimica-Instituto de Tecnologia Quimica UPV-CSIC, Universitat 
      Politecnica de Valencia, Valencia, Spain.
AD  - Unidad Mixta de Investigacion UPV- IIS La Fe, Hospital Universitari i Politecnic 
      La Fe, Valencia, Spain.
LA  - eng
PT  - Journal Article
DEP - 20230607
PL  - Switzerland
TA  - Front Pharmacol
JT  - Frontiers in pharmacology
JID - 101548923
PMC - PMC10283009
OTO - NOTNLM
OT  - anticancer drug
OT  - metabolism
OT  - photodamage to biomolecules
OT  - photosensitized reaction
OT  - tyrosine kinase inhibitor
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2023/06/23 13:07
MHDA- 2023/06/23 13:08
PMCR- 2023/06/07
CRDT- 2023/06/23 10:36
PHST- 2023/04/18 00:00 [received]
PHST- 2023/05/23 00:00 [accepted]
PHST- 2023/06/23 13:08 [medline]
PHST- 2023/06/23 13:07 [pubmed]
PHST- 2023/06/23 10:36 [entrez]
PHST- 2023/06/07 00:00 [pmc-release]
AID - 1208075 [pii]
AID - 10.3389/fphar.2023.1208075 [doi]
PST - epublish
SO  - Front Pharmacol. 2023 Jun 7;14:1208075. doi: 10.3389/fphar.2023.1208075. 
      eCollection 2023.