Mitochondrial (dys)function-a factor underlying the variability of EFV-induced hepatoxicity?
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Otros documentos de la autoría: Polo, Míriam; Alegre, Fernando; Funes, Haryes A.; Blas García, Ana; Víctor, Víctor M.; Esplugues Mota, Juan V.; Apostolova, Nadezda
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http://dx.doi.org/10.1111/bph.13018 |
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Título
Mitochondrial (dys)function-a factor underlying the variability of EFV-induced hepatoxicity?Autoría
Fecha de publicación
2015-01-08Editor
Wiley; British Pharmacological SocietyISSN
0007-1188Cita bibliográfica
POLO, M., et al. Mitochondrial (dys) function–a factor underlying the variability of efavirenz‐induced hepatotoxicity?. British journal of pharmacology, 2015, vol. 172, no 7, p. 1713-1727.Tipo de documento
info:eu-repo/semantics/articleVersión de la editorial
http://onlinelibrary.wiley.com/doi/10.1111/bph.13018/fullVersión
info:eu-repo/semantics/publishedVersionPalabras clave / Materias
Resumen
Background and PurposeThe non-nucleoside analogue reverse transcriptase inhibitor efavirenz is associated with hepatic toxicity and metabolic disturbances. Although the mechanisms involved are not clear, recent evidence ... [+]
Background and PurposeThe non-nucleoside analogue reverse transcriptase inhibitor efavirenz is associated with hepatic toxicity and metabolic disturbances. Although the mechanisms involved are not clear, recent evidence has pinpointed a specific mitochondrial action of efavirenz accompanied by the induction of an endoplasmic reticulum (ER) stress/unfolded protein response in human hepatic cells. The aim of this study was to further investigate the involvement of this organelle by evaluating efavirenz's effects in cells lacking functional mitochondria (rho degrees) and comparing them with those of the typical mitotoxic agent rotenone, a standard complex I inhibitor, and the ER stress inducer thapsigargin.
Experimental ApproachHep3B rho(+) and rho degrees cells were treated with clinically relevant concentrations of efavirenz, then mitochondrial function and cytotoxicity were studied using standard cell biology techniques.
Key ResultsEfavirenz-treated rho degrees cells exhibited a substantial reduction in parameters indicative of mitochondrial interference, such as increased superoxide production, mitochondrial mass/morphology alterations and enhanced expression of LONP, a highly conserved mitochondrial protease. In line with these results, the cytotoxic effect (cell number, chromatin condensation, cell cycle alterations and induction of apoptosis) of efavirenz was less pronounced in Hep3B respiration-depleted cells than in wild-type cells. The effect of efavirenz was both similar and different from those of two distinct mitochondrial stressors, thapsigargin and rotenone.
Conclusions and ImplicationsCells lacking normal mitochondria (rho degrees) are less vulnerable to efavirenz. Our results provide further evidence that the hepatic damage induced by efavirenz involves acute interference with mitochondria and extend our knowledge of the response of mitochondria/ER to a stress stimulus. [-]
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British journal of pharmacology, 2015, vol. 172, no 7Derechos de acceso
© 2014 The British Pharmacological Society
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