Carcinogenic Etheno DNA Adducts in Alcoholic Liver Disease: Correlation with Cytochrome P‐4502E1 and Fibrosis

Mueller, Sebastian; Peccerella, Teresa; Hua, Qi; Glassen, Katharina; Waldherr, Rüdiger; Flechtenmacher, Christa; Straub, Beate K.; Millonig, Gunda; Stickel, Felix; Brückner, Thomas; Bartsch, Helmut; Seitz, Helmut K.

doi:10.1111/acer.13546

Cited by 41 publications

(26 citation statements)

References 49 publications

(55 reference statements)

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“…The pathological role of CYP2E1 has been suggested elsewhere: for example, the deletion of the CYP2E1 gene decreased the development of alcoholic steatohepatitis, non‐alcoholic steatohepatitis, fast food‐mediated hepatofibrosis, and hepatocarcinogenesis, and there is a significant correlation between CYP2E1 determined by immunohistochemically and the stage of hepatofibrosis . Our present study found that higher CYP2E1 activity is a risk factor for hepatocarcinogenesis from hepatofibrosis, which was explained by metabolic activation of DEN.…”

Section: Discussionsupporting

confidence: 74%

From hepatofibrosis to hepatocarcinogenesis: Higher cytochrome P450 2E1 activity is a potential risk factor

Gao

Wang

et al. 2018

Molecular Carcinogenesis

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Hepatofibrosis is an important susceptibility factor for hepatocarcinogenesis. However, only a handful of cases of hepatofibrosis will develop into hepatocellular carcinoma (HCC). As cytochrome P450 2E1 (CYP2E1) is involved in the metabolism and activation of many known environmental toxicants and procarcinogens, this enzyme may play a role in the development of hepatocarcinogenesis subsequent to hepatofibrosis. Herein, we evaluated whether higher CYP2E1 activity is a risk factor for the development of hepatocarcinogenesis from hepatofibrosis. CYP2E1 activity in fibrotic tissues from 72 HCC patients and in normal liver tissues from 59 control subjects was determined along with the severity of hepatofibrosis in hepatocarcinogenesis patients. Similarly, using a rat diethylnitrosamine-induced hepatocarcinogenesis model, CYP2E1 activity at the hepatofibrosis and hepatocarcinogenesis stages was determined, the correlation between CYP2E1 activity at the hepatofibrosis stage and hepatocarcinogenesis was explored, and the impact of inhibition of CYP2E1 activity on hepatocarcinogenesis was studied. The results showed that while CYP2E1 activity in HCC patients with underlying hepatofibrosis was increased, the severity of hepatofibrosis did not correlate with CYP2E1 activity. In the rat hepatocarcinogenesis model, unexpectedly, CYP2E1 activity was found to decrease from hepatofibrosis to hepatocarcinogenesis. Importantly, however, hepatofibrotic rats with higher CYP2E1 activity developed a more severe form of HCC. Moreover, inhibition of CYP2E1 activity could decrease the occurrence and development of HCC in rats. In conclusion, higher CYP2E1 activity may be a risk factor for hepatocarcinogenesis from hepatofibrosis, which raises the possibility of screening patients with hepatofibrosis for CYP2E1 activity to better estimate their risk for hepatocarcinogenesis.

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Section: Discussionsupporting

confidence: 74%

From hepatofibrosis to hepatocarcinogenesis: Higher cytochrome P450 2E1 activity is a potential risk factor

Gao

Wang

et al. 2018

Molecular Carcinogenesis

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“…Can be used as cancer markers [199]. They are carcinogenic and play an important role in initiating the process of hepatocarcinogenesis [200].…”

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confidence: 99%

Oxidative-Antioxidant Imbalance and Impaired Glucose Metabolism in Schizophrenia

et al. 2020

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Schizophrenia is a neurodevelopmental disorder featuring chronic, complex neuropsychiatric features. The etiology and pathogenesis of schizophrenia are not fully understood. Oxidative-antioxidant imbalance is a potential determinant of schizophrenia. Oxidative, nitrosative, or sulfuric damage to enzymes of glycolysis and tricarboxylic acid cycle, as well as calcium transport and ATP biosynthesis might cause impaired bioenergetics function in the brain. This could explain the initial symptoms, such as the first psychotic episode and mild cognitive impairment. Another concept of the etiopathogenesis of schizophrenia is associated with impaired glucose metabolism and insulin resistance with the activation of the mTOR mitochondrial pathway, which may contribute to impaired neuronal development. Consequently, cognitive processes requiring ATP are compromised and dysfunctions in synaptic transmission lead to neuronal death, preceding changes in key brain areas. This review summarizes the role and mutual interactions of oxidative damage and impaired glucose metabolism as key factors affecting metabolic complications in schizophrenia. These observations may be a premise for novel potential therapeutic targets that will delay not only the onset of first symptoms but also the progression of schizophrenia and its complications.

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“…), which may interfere with CYP expression and hepatic drug metabolism. Supporting this, the Heidelberg workgroup found reduced CYP2E1 expression in liver fibrosis, identified with liver stiffness elastography, as well as boosted CYP expression, drug metabolism, and subsequently increased, carcinogenic etheno-DNA adducts in (nonfibrotic) alcoholic liver disease [41, 42]. Therefore, the in-depth evaluation of CYP regulation in liver disease states is also of chief clinical relevance.…”

Section: Discussionmentioning

confidence: 99%

Isoform-Dependent Changes in Cytochrome P450-Mediated Drug Metabolism after Portal Vein Ligation in the Rat

et al. 2018

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Background: Surgical removal of complicated liver tumors may be realized in two stages via selective portal vein ligation, inducing the atrophy of portally ligated lobes and the compensatory hypertrophy of nonligated liver lobes. Unlike morphological changes, functional aspects such as hepatic cytochrome P450 (CYP)-mediated drug metabolism remain vaguely understood, despite its critical role in both drug biotransformation and hepatic functional analysis. Our goal was the multilevel characterization of hepatic CYP-mediated drug metabolism after portal vein ligation in the rat. Methods: Male Wistar rats (n = 24, 210–230 g) were analyzed either untreated (controls; n = 4) or 24/48/72/168/336 h (n = 4 each) following portal vein ligation affecting approximately 80% of the liver parenchyma. Besides the weights of ligated and nonligated lobes, pentobarbital (30 mg/kg)-induced sleeping time, CYP1A(2), CYP 2B(1/2), CYP2C(6/11/13), CYP3A(1) enzyme activities, and corresponding isoform mRNA expressions, as well as CYP3A1 protein expression were determined by in vivo sleeping test, CYP isoform-selective assays, polymerase chain reaction, and immunohistochemistry, respectively. Results: Portal vein ligation triggered atrophy in ligated lobes and hypertrophy nonligated lobes. Sleeping time was transiently elevated (p = 0.0451). After an initial rise, CYP1A, CYP2B, and CYP3A enzyme activities dropped until 72 h, followed by a potent increase only in the nonligated lobes, paralleled by an early (24–48 h) transcriptional activation only in nonligated lobes. CYP2C enzyme activities and mRNA levels were bilaterally rapidly decreased, showing a late reconvergence only in nonligated lobes. CYP3A1 immunohistochemistry indicated substantial differences in positivity in the early period. Conclusions: Beyond the atrophy-hypertrophy complex, portal vein ligation generated a transient suppression of global and regional drug metabolism, re-established by an adaptive, CYP isoform-dependent transcriptional response of the nonligated lobes.

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Carcinogenic Etheno DNA Adducts in Alcoholic Liver Disease: Correlation with Cytochrome P‐4502E1 and Fibrosis

Abstract: These data suggest an important role of CYP2E1 in the generation of εdA, in the fibrotic progression of ALD, and thus in alcohol-mediated hepatocarcinogenesis. CYP2E1 may be a target in the treatment of ALD and a potential prognostic marker for disease progression.

Cited by 41 publications

References 49 publications

From hepatofibrosis to hepatocarcinogenesis: Higher cytochrome P450 2E1 activity is a potential risk factor

From hepatofibrosis to hepatocarcinogenesis: Higher cytochrome P450 2E1 activity is a potential risk factor

Oxidative-Antioxidant Imbalance and Impaired Glucose Metabolism in Schizophrenia

Isoform-Dependent Changes in Cytochrome P450-Mediated Drug Metabolism after Portal Vein Ligation in the Rat

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