title: Protective effect of acetyl-l-carnitine and α-lipoic acid against the acute toxicity of diepoxybutane to human lymphocytes.
abstract: The biotransformation and oxidative stress may contribute to 1,2:3,4-diepoxybutane (DEB)-induced toxicity to human lymphocytes of Fanconi Anemia (FA) patients. Thus, the identification of putative inhibitors of bioactivation, as well as the determination of the protective role of oxidant defenses, on DEB-induced toxicity, can help to understand what is failing in FA cells. In the present work we studied the contribution of several biochemical pathways for DEB-induced acute toxicity in human lymphocyte suspensions, by using inhibitors of epoxide hydrolases, inhibitors of protective enzymes as glutathione S-transferase and catalase, the depletion of glutathione (GSH), and the inhibition of protein synthesis; and a variety of putative protective compounds, including antioxidants, and mitochondrial protective agents. The present study reports two novel findings: (i) it was clearly evidenced, for the first time, that the acute exposure of freshly isolated human lymphocytes to DEB results in severe GSH depletion and loss of ATP, followed by cell death; (ii) acetyl-l-carnitine elicits a significant protective effect on DEB induced toxicity, which was potentiated by α-lipoic acid. Collectively, these findings contribute to increase our knowledge of DEB-induce toxicity and will be very useful when applied in studies with lymphocytes from FA patients, in order to find out a protective agent against spontaneous and DEB-induced chromosome instability.
authors.affiliation: REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Anibal Cunha, 164, 4099-030 Porto, Portugal. filipaponte@gmail.com
authors.forename: Filipa
authors.initials: F
authors.lastname: Ponte
authors.forename: Félix
authors.initials: F
authors.lastname: Carvalho
authors.forename: Beatriz
authors.initials: B
authors.lastname: Porto
mesh_terms: D000108:Acetylcarnitine / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000097:blood; D000328:Adult; D002470:Cell Survival / Q000187:drug effects; D004347:Drug Interactions; D004852:Epoxy Compounds / Q000037:antagonists & inhibitors / Q000633:toxicity*; D005260:Female; D005978:Glutathione / Q000097:blood; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008063:Thioctic Acid / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D004852:Epoxy Compounds; C007366:diepoxybutane; D000108:Acetylcarnitine; D008063:Thioctic Acid; D000255:Adenosine Triphosphate; D005978:Glutathione