title: Disruption of redox homeostasis and carcinogen metabolizing enzymes changes by administration of vitamin E to rats.
abstract: OBJECTIVE
  A large meta-analysis of randomized clinical trials has seriously questioned chemoprevention based on vitamins including vitamin E (VE), and an increased risk for cancer among long-term users was actually seen. However, the mechanism underlying these findings still remain unknown. To clarify the mechanism, in an in vivo model we studied the putative disruption of redox homeostasis and the perturbation of carcinogen metabolizing enzymes determined by VE.
  
  
  METHODS
  Male Sprague-Dawley rats were treated ip with either 100 or 200mg/kg b.w. daily for 7 or 14 consecutive days. Controls received vehicle only. Cytochrome P450 (CYP) content, CYP-reductase, CYP-linked monooxygenases, as well as phase-II and the antioxidant enzymes catalase and
  quinone reductase were investigated in both liver and kidney. Free radical species in tissue subcellular preparations were measured by electronic paramagnetic resonance (EPR) spectroscopy coupled to a radical probe technique.
  
  
  RESULTS
  No substantial changes of hepatic xenobiotic metabolism enzymes were determined by VE. Conversely, a powerful booster effect of various renal phase-I carcinogen bioactivating enzymes at both dosages and observational times was recorded. While no relevant changes of post-oxidative phase-II reactions were found in the liver, a significant inactivating effect was caused by VE in renal tissues. Antioxidant enzymes were found mainly downregulated by the treatment. In the kidney, a marked free radical over-generation linked to CYP induction was observed.
  
  
  CONCLUSIONS
  This study proved that VE acts as a co-carcinogen and pro-oxidant agent. Such epigenetic mechanisms may contribute to explain the harmful outcomes observed in humans.
authors.affiliation: Molecular and Toxicology Unit, Department of Pharmacy and Biotechnology, Alma-Mater Studiorum, University of Bologna, via Irnerio 48, 40126 Bologna, Italy. Electronic address: fabio.vivarelli3@unibo.it.
authors.forename: Fabio
authors.initials: F
authors.lastname: Vivarelli
authors.affiliation: Molecular and Toxicology Unit, Department of Pharmacy and Biotechnology, Alma-Mater Studiorum, University of Bologna, via Irnerio 48, 40126 Bologna, Italy. Electronic address: donatella.canistro@unibo.it.
authors.forename: Donatella
authors.initials: D
authors.lastname: Canistro
authors.affiliation: Department of Chemistry "G. Ciamician", Alma-Mater Studiorum, University of Bologna, Via Selmi 2, 40126 Bologna, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Franchi
authors.affiliation: Molecular and Toxicology Unit, Department of Pharmacy and Biotechnology, Alma-Mater Studiorum, University of Bologna, via Irnerio 48, 40126 Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sapone
authors.affiliation: Institute of Clinical Physiology, CNR, via Moruzzi 1, 56124 Pisa, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Vornoli
authors.affiliation: Institute of Agricultural Biology and Biotechnology, CNR, via Moruzzi 1, 56124 Pisa, Italy.
authors.forename: Clara
authors.initials: C
authors.lastname: Della Croce
authors.affiliation: Institute of Agricultural Biology and Biotechnology, CNR, via Moruzzi 1, 56124 Pisa, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Longo
authors.affiliation: Department of Chemistry "G. Ciamician", Alma-Mater Studiorum, University of Bologna, Via Selmi 2, 40126 Bologna, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Lucarini
authors.affiliation: Molecular and Toxicology Unit, Department of Pharmacy and Biotechnology, Alma-Mater Studiorum, University of Bologna, via Irnerio 48, 40126 Bologna, Italy.
authors.forename: Moreno
authors.initials: M
authors.lastname: Paolini
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D002273:Carcinogens / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction / Q000187:drug effects*; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D014810:Vitamin E / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology
chemical_list: D016588:Anticarcinogenic Agents; D002273:Carcinogens; D017382:Reactive Oxygen Species; D014810:Vitamin E; D003577:Cytochrome P-450 Enzyme System
keywords: Antioxidant enzymes; Chemopreventive agent; Cytochrome P450; Free radical species; Phase II enzymes; Vitamin E