title: Possible Mechanisms of Ethanol-Mediated Colorectal Carcinogenesis: The Role of Cytochrome P4502E1, Etheno-DNA Adducts, and the Anti-Apoptotic Protein Mcl-1.
abstract: Chronic alcohol consumption is a risk factor for colorectal cancer. The mechanisms by which ethanol (EtOH) exerts its carcinogenic effect on the colorectal mucosa are not clear and may include oxidative stress with the action of reactive oxygen species (ROS) generated through EtOH metabolism via cytochrome P4502E1 (CYP2E1) leading to carcinogenic etheno-DNA adducts. ROS may also induce apoptosis. However, the effect of chronic EtOH consumption on CYP2E1, etheno-DNA adducts as well as anti-apoptotic proteins in the colorectal mucosa of heavy drinkers without colorectal inflammation is still not known.
  
  
  
  Rectal biopsies from 32 alcoholics (>60 g EtOH/d) and from 12 controls (<20 g EtOH/d) were histologically examined, and immunohistochemistry for CYP2E1 and etheno-DNA adducts was performed. Apoptosis (cleaved PARP) as well as anti-apoptotic proteins including Bcl-xL, Bcl-2, and Mcl-1 were immunohistochemically determined.
  
  
  
  No significant difference in mucosal CYP2E1 or etheno-DNA adducts was observed between alcoholics and control patients. However, CYP2E1 and etheno-DNA adducts correlated significantly when both groups were combined (p < 0.001). In addition, although apoptosis was found not to be significantly affected by EtOH, the anti-apoptotic protein Mcl-1, but neither Bcl-xLnor Bcl-2, was found to be significantly increased in heavy drinkers as compared to controls (p = 0.014).
  
  
  
  Although colorectal CYP2E1 was not found to be significantly increased in alcoholics, CYP2E1 correlated overall with the level of etheno-DNA adducts in the colorectal mucosa, which identifies CYP2E1 as an important factor in colorectal carcinogenesis. Most importantly, however, is the up-regulation of the anti-apoptotic protein Mcl-1 in heavy drinkers counteracting apoptosis and possibly stimulating cancer development.
authors: National Tumor Centre, University of Heidelberg, Heidelberg, Germany.
authors: Bruno Christian
authors: BC
authors: Koehler
authors: Centre of Alcohol Research (CAR), University of Heidelberg, Heidelberg, Germany.|Department of Medicine, Salem Medical Centre, Heidelberg, Germany.
authors: Tatjana
authors: T
authors: Arslic-Schmitt
authors: Centre of Alcohol Research (CAR), University of Heidelberg, Heidelberg, Germany.
authors: Theresa
authors: T
authors: Peccerella
authors: National Tumor Centre, University of Heidelberg, Heidelberg, Germany.
authors: Anna-Lena
authors: AL
authors: Scherr
authors: National Tumor Centre, University of Heidelberg, Heidelberg, Germany.
authors: Henning
authors: H
authors: Schulze-Bergkamen
authors: Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany.
authors: Thomas
authors: T
authors: Bruckner
authors: Department of Pathology, University of Heidelberg, Heidelberg, Germany.
authors: Georg
authors: G
authors: Gdynia
authors: National Tumor Centre, University of Heidelberg, Heidelberg, Germany.
authors: Dirk
authors: D
authors: Jäger
authors: Centre of Alcohol Research (CAR), University of Heidelberg, Heidelberg, Germany.|Department of Medicine, Salem Medical Centre, Heidelberg, Germany.
authors: Sebastian
authors: S
authors: Mueller
authors: Erstwhile: Division of Toxicology and Cancer Risk Factors, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors: Helmut
authors: H
authors: Bartsch
authors: Centre of Alcohol Research (CAR), University of Heidelberg, Heidelberg, Germany. helmut_karl.seitz@urz.uni-heidelberg.de.|Department of Medicine, Salem Medical Centre, Heidelberg, Germany. helmut_karl.seitz@urz.uni-heidelberg.de.
authors: Helmut K
authors: HK
authors: Seitz
mesh_terms: D000368:Aged; D000437:Alcoholism / Q000150:complications / Q000378:metabolism*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D063646:Carcinogenesis / Q000139:chemically induced*; D016022:Case-Control Studies; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D018736:DNA Adducts / Q000378:metabolism*; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D012007:Rectum / Q000187:drug effects / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D018736:DNA Adducts; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1
keywords: Alcohol; Colorectal Cancer; Cytochrome P4502E1; Etheno-DNA Adducts; Mcl-1