Elsevier

Journal of Hepatology

Volume 33, Issue 6, December 2000, Pages 893-901
Journal of Hepatology

Cytochromes P450 2A6, 2E1, and 3A and production of protein-aldehyde adducts in the liver of patients with alcoholic and non-alcoholic liver diseases

https://doi.org/10.1016/S0168-8278(00)80120-8Get rights and content

Abstract

Background/Aims: Interaction between CYP2E1, ethanol metabolites, and enhanced lipid peroxidation is linked to the pathogenesis of alcoholic liver disease. This study was conducted to compare the expression of various cytochrome enzymes and the appearance of aldehyde adducts in humans.

Methods: Acetaldehyde- and lipid peroxidation-derived protein adducts and CYP2A6, 2E1, and 3A4/5 were examined immunohistochemically from liver specimens of 12 alcohol abusers with either mild (n=7) or severe (n=5) liver disease, and from nine non-drinking patients with non-alcoholic steatosis (n=4), or hepatitis (n=5).

Results: Ethanol-inducible CYP2E1 was present in all alcoholic livers. While CYP2A6 in zone 3 hepatocytes was also abundant in the alcoholic patients with various degrees of liver disease, CYP3A4/5 was most prominent in alcoholic cirrhosis. The sites of CYP2E1 and CYP2A6 immunoreactivity co-localized with fatty deposits, and with the sites of acetaldehyde and lipid peroxidation-derived protein adducts. The CYP enzymes were also abundant in the centrilobular hepatocytes of patients with fatty liver due to obesity or diabetes.

Conclusions: Alcohol-induced liver damage is associated with a generalized induction of CYP2A6, CYP2E1 and CYP3A4 and generation of acetaldehyde and lipid peroxidation-derived protein-aldehyde adducts. However, CYP induction also occurred in patients with non-alcoholic steatosis.

Section snippets

Patients

The present study protocol and the use of human tissue samples was approved by the Ethics Committee of the University of Oulu, and the study was carried out according to the principles of the Declaration of Helsinki. The study subjects were patients undergoing surgery or liver biopsy. In all of them a liver biopsy was necessary for routine diagnostic purposes. Prior to the study, informed consent was obtained from each subject.

Liver biopsies were obtained from 12 patients with a history of

Results

The present sample of alcoholic patients consisted of 12 patients with either early-phase (n=7) or advanced liver disease (n=5), and of nine patients with non-alcoholic fatty liver (n=4) or hepatitis (n=5). The relevant clinical and biochemical data of the study subjects are summarized in Table 1.

The cellular distribution and the amount of various CYP forms was found to vary between the different study groups. Results of the immunohistochemical stainings for CYP2E1, CYP2A, and CYP3A in the

Discussion

A major finding that emerged from this study is the increase of multiple CYPs, CYP2E1, CYP2A and CYP3A, in human alcoholic liver disease (ALD). Increased expression of the different CYP forms occurred concomitantly with the formation of protein adducts with acetaldehyde, the first metabolite of ethanol, and malondialdehyde, a product of lipid peroxidation. The acinar distributions of CYP2E1 and CYP2A were also found to follow those of the protein adducts and steatosis, suggesting that the

Acknowledgements

We are indebted to Prof. Seppo Ylä-Herttuala, University of Kuopio for providing the anti-MDA-adduct antibodies. The expert technical assistance of Mrs. Lissu Hukkanen is gratefully acknowledged. The study was supported by the Finnish Foundation for Alcohol Studies, The Academy of Finland grants no. 34555, 29456, and by the European Council, Biomed 2 Program (EUROCYP).

References (51)

  • P Arvela et al.

    The cerium induced liver injury and oxidative drug metabolism in DBA/2 and C57BL/6 mice

    Toxicology

    (1991)
  • P Pellinen et al.

    Modification of hepatic cytohrome P450 profile by cocaine-induced hepatotoxicity in DBA/2 mouse

    Eur J Pharmacol Environ Toxicol Pharmacol Section

    (1994)
  • AM Camus-Randon et al.

    Liver injury and expression of cytochromes P450: evidence that regulation of CYP2A5 is different from that of other major xenobiotic metabolizing CYP enzymes

    Toxicol Appl Pharmacol

    (1996)
  • P Pelkonen et al.

    Activation of aflatoxin B1 by mouse CYP2A enzymes and cytotoxicity in recombinant yeast cells

    Eur J Pharmacol

    (1994)
  • UJ Behrens et al.

    Formation of acetaldehyde adducts with ethanol-inducible P450IIE1 in vivo

    Biochem Biophys Res Commun

    (1988)
  • P Clot et al.

    Cytochrome P4502E1 hydroxyethyl radical adducts as the major antigen in autoantibody formation among alcoholics

    Gastroenterology

    (1996)
  • J-S Yoo et al.

    Regulation of hepatic microsomal cytochrome P450IIE1 level by dietary lipids and carbohydrates in rats

    J Nutr

    (1991)
  • A Kojo et al.

    Distinct responses of mouse hepatic CYP enzymes to corn oil and peroxisome proliferators

    Biochem Pharmacol

    (1996)
  • CS Lieber

    Biochemical and molecular basis of alcohol-induced injury to liver and other tissues

    N Engl J Med

    (1988)
  • SL Smith et al.

    Acetaldehyde substoichiometrically inhibits bovine neurotubulin polymerization

    J Clin Invest

    (1989)
  • O Niemelä et al.

    Immunohistochemical demonstration of acetaldehyde containing epitopes in human liver after ethanol ingestion

    J Clin Invest

    (1991)
  • A Holstege et al.

    Acetaldehyde-modified epitopes in liver biopsy specimens of alcoholic and nonalcoholic patients: localization and association with progression of liver fibrosis

    Hepatology

    (1994)
  • O Niemelä et al.

    Sequential acetaldehyde production, lipid peroxidation and fibrogenesis in micropig model of alcohol-induced liver disease

    Hepatology

    (1995)
  • H Tsukamoto et al.

    Experimental liver disease induced by alcohol and iron

    J Clin Invest

    (1995)
  • J Fraenkel-Konrad et al.

    Nucleoside adducts are formed by cooperative reaction of acetaldehyde and alcohols: a possible mechanism for the role of alcohol in carcinogenesis

    Proc Natl Acad Sci USA

    (1988)
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