The intralobular distribution of ethanol-inducible P450IIE1 in rat and human liver

Tsutsumi, Mikihiro; Lasker, Jerome M.; Shimizu, Masanori; Rosman, Alan S.; Lieber, Charles S.

doi:10.1002/hep.1840100407

Cited by 295 publications

(121 citation statements)

References 36 publications

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“…That mechanism accounts for ethanol potentiation of CCl 4 hepatotoxicity. 24,25 Finally, CYP2E1 knockout mice are resistant to hepatoxicity induced by CCl 4 . 21 We asked whether p8 could interfere with the regulation of CYP2E1 gene expression.…”

Section: Resultsmentioning

confidence: 99%

Inactivation of Stress Protein p8 Increases Murine Carbon Tetrachloride Hepatotoxicity via Preserved CYP2E1 Activity *

et al. 2005

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The p8 protein is a transcription factor that regulates the expression of genes involved in cell defense against the adverse effects of stress. Its expression is strongly, rapidly, and transiently induced in most cells on exposure to various stress agents. This study assessed the role of p8 in the response of the liver to CCl 4 -induced injury. We found that p8 was indeed overexpressed in the liver after CCl 4 administration. Hepatic injury following CCl 4 injection was monitored in wild-type and p8 ؊/؊ mice. Serum alanine and aspartate aminotransferase activities were higher and peaked earlier in p8 ؊/؊ mice than in wild-type mice, which is in agreement with the observation of significantly larger areas of necrosis in p8 ؊/؊ liver. Absence of p8 expression is therefore associated with increased liver sensitivity to CCl 4 . In fact, CCl 4 toxicity is mediated by derivatives generated by its conversion by the enzyme CYP2E1. It is known that CYP2E1 is downregulated in the liver during the first hours following CCl 4 administration as part of a self-defense mechanism. We found that CYP2E1 downregulation was significantly delayed in p8 ؊/؊ liver compared with wild-type liver, allowing increased production of toxic CCl 4 derivatives. In conclusion, inactivation of the p8 gene increases liver sensitivity to CCl 4 , as it appears to delay the triggering of CYP2E1 downregulation. The p8 protein is therefore an important element of hepatocyte stress response. (HEPATOLOGY 2005;42:176-182.)

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Section: Resultsmentioning

confidence: 99%

Inactivation of Stress Protein p8 Increases Murine Carbon Tetrachloride Hepatotoxicity via Preserved CYP2E1 Activity *

et al. 2005

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“…The positional heterogeneity of gene expression in the postpartum liver has been well documented for several genes (Bass et al, 1989;Tsutsumi et al, 1989;Moorman et al, 1990a,b;Marti and Gebhardt, 1991;Buhler et al, 1992). However, the transcriptional control mechanisms that mediate zonal gene expression within the liver acinus have yet to be identified.…”

Section: Discussionmentioning

confidence: 99%

The zonal expression of α‐fetoprotein transgenes in the livers of adult mice

Emerson

Vacher

Cirillo

et al. 1992

Developmental Dynamics

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The developmental regulation of the a-fetoprotein (AFP) gene in liver results in high-level expression in the fetus, followed by dramatic transcriptional repression after birth. We have examined the mouse AFP gene for transcriptional control sequences that may be involved in its postnatal repression in liver. We showed previously that removal of a DNA region between positions -250 base pairs (bp) and -838 bp of the AFP gene resulted in the persistence of expression of an AFP minigene in the postpartum liver of transgenic mice (Vacher and Tilghman, Science 2501732-1735,1990). This study examines the distribution of these transgene transcripts in liver using in situ hybridization. We show that there is a zonal distribution of minigene transcripts in the adult livers of these animals. Hepatocytes surrounding the central veins express high levels of minigene transcripts, while hepatocytes in the intermediate and portal areas contain few, if any, transcripts. Quantitative RNAse protection analysis shows a decrease in transgene RNA levels after birth, consistent with repression in all but a small subset of hepatocytes. These results indicate that repression in the pericentral hepatocytes is dependent upon the presence of a cis-acting, negative-regulatory domain, which is located between the enhancers and the proximal promoter of the AFP gene. In contrast, this domain is not essential for complete repression of AFP transgenes in the intermediate zone and periportal hepatocytes. o 1992 Wiley-Liss, Inc.

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“…Representative pictures were taken at a magnification of 200ϫ with a Leica Image Manager 50 (Leica, Solms, Germany) and analyzed using Image J software (Toronto Western Research Institute, UK). The frequency of ⑀dA and ⑀dC positively stained nuclei was expressed as a percentage of stained cell nuclei over the total number of cells counted Staining intensity for CYP2E1 and 4-HNE was assessed according to the scale devised by Tsutsumi et al, 21 whereby 3ϩ, 2ϩ, 1ϩ, and 0 denote intense, moderate, slight, and no specific immunostaining, respectively.…”

Section: Methodsmentioning

confidence: 99%

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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The intralobular distribution of ethanol-inducible P450IIE1 in rat and human liver

Cited by 295 publications

References 36 publications

Inactivation of Stress Protein p8 Increases Murine Carbon Tetrachloride Hepatotoxicity via Preserved CYP2E1 Activity *

Inactivation of Stress Protein p8 Increases Murine Carbon Tetrachloride Hepatotoxicity via Preserved CYP2E1 Activity *

The zonal expression of α‐fetoprotein transgenes in the livers of adult mice

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

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