title: Inhibition of alcohol-associated colonic hyperregeneration by alpha-tocopherol in the rat.
abstract: BACKGROUND
  Chronic alcohol consumption results in colorectal mucosal hyperregeneration, a condition associated with an increased risk for colorectal cancer. Possible mechanisms may involve the effects of acetaldehyde and/or free radicals generated during alcohol metabolism. Vitamin E is part of the antioxidative defense system, and its concentration is decreased or its metabolic utilization increased in various tissues after chronic alcohol consumption. We wondered whether alpha-tocopherol supplementation may prevent ethanol-induced colorectal cell cycle behavior and whether these changes were related to alterations in protein synthesis.
  
  
  METHODS
  Five groups of male Wistar rats, each consisting of 14 animals, received liquid diets as follows: group 1, alcohol; group 2, alcohol + alpha-tocopherol; group 3, control (i.e., isocaloric glucose); group 4; control (i.e., isocaloric glucose) + alpha-tocopherol. Group 5 was fed a solid chow diet ad libitum. After 4 weeks of feeding, immunohistology was performed with anti-proliferating cell nuclear antigen (PCNA) or anti-BCL2 antibodies. Fractional (k(s)) and absolute (V(s)) rates of protein synthesis and rates of protein synthesis relative to RNA (k(RNA)) and DNA (k(DNA)) were measured with a flooding dose of L-[4-3H] phenylalanine with complementary analysis of protein and nucleic acid composition.
  
  
  RESULTS
  The PCNA index was increased significantly in the colon after ethanol administration compared with controls (ethanol, 10.3 +/- 2.3 vs. control, 6.51 +/- 1.6% PCNA positive cells, p < 0.05), although neither the protein, RNA, and DNA concentrations nor k(s), k(RNA), k(DNA), and V(s) were affected. This increase in PCNA index was significantly diminished by coadministration of alpha-tocopherol (ethanol + alpha tocopherol, 7.86 +/- 1.71% PCNA positive cells, p < 0.05) without significant alterations in protein synthetic parameters. A similar result was obtained for the PCNA index in the rectal mucosa (ethanol, 14.6 +/- 4.4 vs. control, 12.1 +/- 4.2% PCNA positive cell), although this did not reach statistical significance. Neither ethanol nor alpha tocopherol feeding had any significant effect on BCL-2 expression in the colorectal mucosa. As with the colon, protein synthetic parameters in the mucosa were not affected by alcohol feeding at 4 weeks. These effects on colonic cell turnover without corresponding changes in protein synthesis thus represent a specific localized phenomenon rather than a general increase in anabolic processes in the tissue and reaffirm the hyperregenerative properties of chronic alcohol consumption.
  
  
  CONCLUSIONS
  Alcohol-associated hyperproliferation could be prevented, at least in part, by supplementation with alpha-tocopherol. This may support the hypothesis that free radicals are involved in the pathogenesis of alcohol-associated colorectal hyperproliferation.
authors.affiliation: Laboratory of Alcohol Research, Liver Disease and Nutrition and Department of Medicine, Salem Medical Center, Heidelberg, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Vincon
authors.forename: J
authors.initials: J
authors.lastname: Wunderer
authors.forename: U A
authors.initials: UA
authors.lastname: Simanowski
authors.forename: M
authors.initials: M
authors.lastname: Koll
authors.forename: V R
authors.initials: VR
authors.lastname: Preedy
authors.forename: T J
authors.initials: TJ
authors.lastname: Peters
authors.forename: J
authors.initials: J
authors.lastname: Werner
authors.forename: R
authors.initials: R
authors.lastname: Waldherr
authors.forename: H K
authors.initials: HK
authors.lastname: Seitz
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003106:Colon / Q000187:drug effects* / Q000473:pathology*; D000431:Ethanol / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D024502:alpha-Tocopherol / Q000494:pharmacology*
chemical_list: D000431:Ethanol; D024502:alpha-Tocopherol