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Singlet oxygen and radical-mediated mechanisms in the oxidative cellular damage photosensitized by the protease inhibitor simeprevir

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Singlet oxygen and radical-mediated mechanisms in the oxidative cellular damage photosensitized by the protease inhibitor simeprevir

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dc.contributor.author García-Laínez, Guillermo es_ES
dc.contributor.author El Ouardi, Meryem es_ES
dc.contributor.author Moreno, Alejandro es_ES
dc.contributor.author Lence, Emilio es_ES
dc.contributor.author González-Bello, Concepción es_ES
dc.contributor.author Miranda, Miguel Á. es_ES
dc.contributor.author Andreu, Inmaculada es_ES
dc.date.accessioned 2024-04-11T07:22:08Z
dc.date.available 2024-04-11T07:22:08Z
dc.date.issued 2023-01 es_ES
dc.identifier.issn 0891-5849 es_ES
dc.identifier.uri http://hdl.handle.net/10251/203295
dc.description.abstract [EN] Hepatitis C, a liver inflammation caused by the hepatitis C virus (HCV), is treated with antiviral drugs. In this context, simeprevir (SIM) is an NS3/4A protease inhibitor used in HCV genotypes 1 and 4. It is orally admin-istered and achieves high virological cure rates. Among adverse reactions associated with SIM treatment, photosensitivity reactions have been reported. In the present work, it is clearly shown that SIM is markedly phototoxic, according to the in vitro NRU assay using BALB/c 3T3 mouse fibroblast. This result sheds light on the nature of the photosensitivity reactions induced by SIM in HCV patients, suggesting that porphyrin elevation in patients treated with SIM may not be the only mechanism responsible for SIM-associated photosensitivity. Moreover, lipid photoperoxidation and protein photooxidation assays, using human skin fibroblasts (FSK) and human serum albumin (HSA), respectively, reveal the capability of this drug to promote photodamage to cellular membranes. Also, DNA photo lesions induced by SIM are noticed through comet assay in FSK cells. Photo-chemical and photobiological studies on the mechanism of SIM-mediated photodamage to biomolecules indicate that the key transient species generated upon SIM irradiation is the triplet excited state. This species is efficiently quenched by oxygen giving rise to singlet oxygen, which is responsible for the oxidation of lipids and DNA (Type II mechanism). In the presence of HSA, the photobehavior is dominated by binding to site 3 of the protein, to give a stable SIM@HSA complex. Inside the complex, quenching of the triplet excited state is less efficient, which results in a longer triplet lifetime and in a decreased singlet oxygen formation. Hence, SIM-mediated photoox-idation of the protein is better explained through a radical (Type I) mechanism. es_ES
dc.description.sponsorship Financial support from the Spanish Ministry of Science and Innovation [PID2020-115010RB-I00/AEI/10.13039/501100011033 (I.A), PID2019-105512RB-I00/AEI/10.13039/501100011033 (CG-B) and FPU predoctoral fellowship for M. El O.], Axencia Galega de Innovacion (2020-PG067, CG-B), the Xunta de Galicia [ED431C 2021/29 and the Centro singular de investigacion de Galicia accreditation 2019-2022 (ED431G 2019/03),], and the European Regional Development Fund (ERDF) is gratefully acknowledged. All authors are grateful to the Centro de Supercomputacion de Galicia (CESGA) for use of the Finis Terrae computer. es_ES
dc.language Inglés es_ES
dc.publisher Elsevier es_ES
dc.relation.ispartof Free Radical Biology and Medicine es_ES
dc.rights Reconocimiento - No comercial (by-nc) es_ES
dc.subject Antiviral agent es_ES
dc.subject Binding to proteins es_ES
dc.subject Cellular photo(geno)toxicity es_ES
dc.subject Photodamage to biomolecules es_ES
dc.subject Triplet excited state es_ES
dc.subject.classification QUIMICA ORGANICA es_ES
dc.title Singlet oxygen and radical-mediated mechanisms in the oxidative cellular damage photosensitized by the protease inhibitor simeprevir es_ES
dc.type Artículo es_ES
dc.identifier.doi 10.1016/j.freeradbiomed.2022.11.006 es_ES
dc.relation.projectID info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-105512RB-I00/ES/COMBATIENDO LAS BACTERIAS RESISTENTES A LOS ANTIBIOTICOS Y CONTROLANDO SU EVOLUCION IN VIVO MEDIANTE ESTRATEGIAS INNOVADORAS Y NUEVOS TESTS DE DIAGNOSTICO CLINICO/ es_ES
dc.relation.projectID info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-115010RB-I00/ES/FOTOCOMPORTAMIENTO DE LOS INHIBIDORES DE LA TIROSINA QUINASA: DE DISOLUCION A CELULAS/ es_ES
dc.relation.projectID info:eu-repo/grantAgreement/Xunta de Galicia//ED431G 2019%2F03/ es_ES
dc.relation.projectID info:eu-repo/grantAgreement/GAIN//2020-PG067/ es_ES
dc.rights.accessRights Abierto es_ES
dc.contributor.affiliation Universitat Politècnica de València. Escuela Técnica Superior de Ingenieros Industriales - Escola Tècnica Superior d'Enginyers Industrials es_ES
dc.description.bibliographicCitation García-Laínez, G.; El Ouardi, M.; Moreno, A.; Lence, E.; González-Bello, C.; Miranda, MÁ.; Andreu, I. (2023). Singlet oxygen and radical-mediated mechanisms in the oxidative cellular damage photosensitized by the protease inhibitor simeprevir. Free Radical Biology and Medicine. 194:42-51. https://doi.org/10.1016/j.freeradbiomed.2022.11.006 es_ES
dc.description.accrualMethod S es_ES
dc.relation.publisherversion https://doi.org/10.1016/j.freeradbiomed.2022.11.006 es_ES
dc.description.upvformatpinicio 42 es_ES
dc.description.upvformatpfin 51 es_ES
dc.type.version info:eu-repo/semantics/publishedVersion es_ES
dc.description.volume 194 es_ES
dc.identifier.pmid 36375737 es_ES
dc.relation.pasarela S\479150 es_ES
dc.contributor.funder Xunta de Galicia es_ES
dc.contributor.funder Ministerio de Universidades es_ES
dc.contributor.funder Axencia Galega de Innovación es_ES
dc.contributor.funder AGENCIA ESTATAL DE INVESTIGACION es_ES
dc.contributor.funder Agencia Estatal de Investigación es_ES
dc.contributor.funder European Regional Development Fund es_ES
dc.contributor.funder Universitat Politècnica de València es_ES


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