Dynamics of cytochrome P4502E1 activity in man: induction by ethanol and disappearance during withdrawal phase

Oneta, Carl; Lieber, Charles S.; Li, Junjie; Rüttimann, S; Schmid, B.; J, Lattmann; Rosman, Alan S.; Seitz, Helmut K.

doi:10.1016/s0168-8278(01)00223-9

Cited by 165 publications

(124 citation statements)

References 25 publications

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“…As already pointed out, 12 the intensity of CYP2E1 expression varies substantially between alcohol consumers for yet unknown reasons. However, the low inducibility of CYP2E1 in some individuals may represent a protective factor in relation to ethanol-mediated carcinogenesis.…”

Section: Discussionmentioning

confidence: 92%

“…11 CYP2E1 is induced by chronic alcohol consumption within a week even at a relatively low ethanol dose (40 g/d), but the degree of CYP2E1 induction varies substantially between individuals. 12 Inhibition of CYP2E1 by chlormethiazole (CMZ), a specific CYP2E1 inhibitor, improved alcoholic liver disease (ALD) as shown in the Tsukamoto-French rat model. 13 An increase of oxidative DNA adducts and of mutagenic apurinic and apyrimidinic DNA sites were found in wild-type mice chronically fed ethanol, but not in mice knocked out for functional CYP2E1, 14 further highlighting the importance of CYP2E1 in the generation of DNA damage after ethanol ingestion.…”

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confidence: 99%

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Ethanol‐induced cytochrome P4502E1 causes carcinogenic etheno‐DNA lesions in alcoholic liver disease†‡

et al. 2009

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Oxidative stress is thought to play a major role in the pathogenesis of hepatocellular cancer (HCC), a frequent complication of alcoholic liver disease (ALD). However, the underlying mechanisms are poorly understood. In hepatocytes of ALD patients, we recently detected by immunohistochemistry significantly increased levels of carcinogenic etheno-DNA adducts that are formed by the reaction of the major lipid peroxidation product, 4-hydroxynonenal (4-HNE) with nucleobases. In the current study, we show that protein-bound 4-HNE and etheno-DNA adducts both strongly correlate with cytochrome P450 2E1 (CYP2E1) expression in patients with ALD (r ‫؍‬ 0.9, P < 0.01). Increased levels of etheno-DNA adducts were also detected in the liver of alcohol-fed lean ( E xcess consumption of alcohol is widespread inWestern countries and, in the United States, alcohol abuse affects approximately 18 million adults. 1 The consumption of more than 80 g ethanol per day for more than 10 years increases the risk for hepatocellular carcinoma (HCC) by approximately fivefold. 2 Worldwide, HCC is one of the most common malignant tumors, ranking as the seventh most prevalent in men and the ninth in women. The risk for HCC in decompensated alcohol-induced cirrhosis is approximately 1% to 2% per year. 2 Although the evolution of alcohol-related HCC involves several factors, 3,4 including the presence of cirrhosis, oxidative stress, disturbed DNA methylation, and defective retinoic acid signaling, the precise mechanisms at a molecular level by which alcohol causes HCC are poorly understood. Recently, the International Agency for Research on Cancer has classified ethanol as a human (group 1) carcinogen, because it induces HCC (among other tumors) in animals and increases the risk for developing HCC in humans. 3,5,6

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Section: Discussionmentioning

confidence: 92%

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confidence: 99%

Ethanol‐induced cytochrome P4502E1 causes carcinogenic etheno‐DNA lesions in alcoholic liver disease†‡

et al. 2009

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“…30 Upregulation of CYP2E1 in human ALD was not expected as these patients had been abstinent in the period leading up to liver transplantation and in experimental animals, induction of CYP2E1 disappears within 3 days of alcohol withdrawal. 31 Thus the effects of recent alcohol consumption were more evident in the baboon model because the samples were obtained during ongoing alcohol treatment. In this model, genes involved in alcohol metabolism were prominently differentially expressed to a greater extent than in the samples obtained from abstinent humans with advanced disease.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling of Alcoholic Liver Disease in the Baboon (Papio hamadryas) and Human Liver

Seth¹,

Leo²,

McGuinness³

et al. 2003

The American Journal of Pathology

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The molecular pathogenesis of alcoholic liver disease (ALD) is not well understood. Gene expression profiling has the potential to identify new pathways and altered molecules in ALD. Gene expression profiles of ALD in a baboon model and humans were compared using DNA arrays. Reverse transcriptase-polymerase chain reaction and immunohistochemistry were used for downstream analysis of array results. cDNA array analysis revealed differential expression of several novel genes and pathways in addition to genes known to be involved in ALD pathogenesis. Overall gene expression profiles were similar in both species, with a majority of genes involved with fibrogenesis and xenobiotic metabolism, as well as inflammation, oxidant stress, and cell signaling. Genes associated with stellate cell activation (collagens, matrix metalloproteinases, tissue inhibitors of matrix metalloproteinase) were up-regulated in humans. Decreased expression of several metallothioneins was unexpected.

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“…In humans, the extent of CYP2E1 induction is individually determined, but may be significant following the ingestion of 40 g alcohol per day, corresponding to 400 ml of 12.5 vol.% wine, for 1 week (Oneta et al, 2002). ROS produced by CYP2E1 lead to lipid peroxidation, with the generation of malondialdehyde (MDA) and 4-HNE (Aleynik et al, 1998).…”

Section: Acetaldehydementioning

confidence: 99%

Risk factors and mechanisms of hepatocarcinogenesis with special emphasis on alcohol and oxidative stress

Seitz

Stickel

2006

Biological Chemistry

282

178

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Hepatocellular cancer is the fifth most frequent cancer in men and the eighth in women worldwide. Established risk factors are chronic hepatitis B and C infection, chronic heavy alcohol consumption, obesity and type 2 diabetes, tobacco use, use of oral contraceptives, and aflatoxin-contaminated food. Almost 90% of all hepatocellular carcinomas develop in cirrhotic livers. In Western countries, attributable risks are highest for cirrhosis due to chronic alcohol abuse and viral hepatitis B and C infection. Among those with alcoholic cirrhosis, the annual incidence of hepatocellular cancer is 1-2%. An important mechanism implicated in alcohol-related hepatocarcinogenesis is oxidative stress from alcohol metabolism, inflammation, and increased iron storage. Ethanolinduced cytochrome P-450 2E1 produces various reactive oxygen species, leading to the formation of lipid peroxides such as 4-hydroxy-nonenal. Furthermore, alcohol impairs the antioxidant defense system, resulting in mitochondrial damage and apoptosis. Chronic alcohol exposure elicits hepatocyte hyperregeneration due to the activation of survival factors and interference with retinoid metabolism. Direct DNA damage results from acetaldehyde, which can bind to DNA, inhibit DNA repair systems, and lead to the formation of carcinogenic exocyclic DNA etheno adducts. Finally, chronic alcohol abuse interferes with methyl group transfer and may thereby alter gene expression.

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Dynamics of cytochrome P4502E1 activity in man: induction by ethanol and disappearance during withdrawal phase

Cited by 165 publications

References 25 publications

Ethanol‐induced cytochrome P4502E1 causes carcinogenic etheno‐DNA lesions in alcoholic liver disease†‡

Ethanol‐induced cytochrome P4502E1 causes carcinogenic etheno‐DNA lesions in alcoholic liver disease†‡

Gene Expression Profiling of Alcoholic Liver Disease in the Baboon (Papio hamadryas) and Human Liver

Risk factors and mechanisms of hepatocarcinogenesis with special emphasis on alcohol and oxidative stress

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