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Mitochondrial CYP2E1 is sufficient to mediate oxidative stress and cytotoxicity induced by ethanol and acetaminophen.

By Laetitia Knockaert, Véronique Descatoire, Nathalie Vadrot, Bernard Fromenty and Marie-Anne Robin

Abstract

International audienceSeveral cytochromes P450 (CYPs) are not only located in the endoplasmic reticulum but also within mitochondria. One such CYP is CYP2E1 which metabolizes numerous substrates and generates significant amount of reactive oxygen species. The presence of CYP2E1 in these organelles raises questions regarding its physiological role but also its possible deleterious effects in the context of drug-induced cytotoxicity. The aim of our study was to investigate the role of mitochondrial CYP2E1 in the toxicity of acetaminophen and ethanol. Hence the effects of these two compounds in cells expressing CYP2E1 in mitochondria only, or in both endoplasmic reticulum and mitochondria, were compared to those observed in mock-transfected cells. Our results indicated that when acetaminophen or ethanol were used as CYP2E1 substrates, the exclusive localization of CYP2E1 within mitochondria was sufficient to induce reactive oxygen species overproduction, depletion of reduced glutathione, increased expression of mitochondrial Hsp70, mitochondrial dysfunction and cytotoxicity. Importantly, these harmful events happened despite lower cellular level and activity of CYP2E1 when compared to cells expressing CYP2E1 in both endoplasmic reticulum and mitochondria, and this was particularly obvious with acetaminophen. Taken together, these data suggest that mitochondrial CYP2E1 could play a major role in drug-induced oxidative stress and cell demise

Topics: Cytochrome P450 2E1, Mitochondria, Reactive oxygen species, Ethanol, Acetaminophen, MESH : Acetaminophen, MESH : Analgesics, Non-Narcotic, MESH : Membrane Potential, Mitochondrial, MESH : Oxidative Stress, MESH : Oxygen Consumption, MESH : Reactive Oxygen Species, MESH : Superoxide Dismutase, MESH : Animals, MESH : COS Cells, MESH : Cell Survival, MESH : Cercopithecus aethiops, MESH : Cytochrome P-450 CYP2E1, MESH : Ethanol, MESH : Glutathione, MESH : HSP70 Heat-Shock Proteins, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology
Publisher: Elsevier
Year: 2011
DOI identifier: 10.1016/j.tiv.2010.11.019
OAI identifier: oai:HAL:hal-00739823v1
Provided by: Hal-Diderot
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