Overexpression of CYP2E1 enhances sensitivity of HepG2 cells to Fas-mediated cytotoxicity

Qu, Yan; Shi, Jianguo; Zhang, Feng; Zhao, Qing-tao; Pang, Xiaowu; Chen, Rui; Hu, Peizhen; Li, Qin-Long; Wang, Zhe; Huang, Guoxin

doi:10.4161/cbt.7.8.6283

Cited by 8 publications

(7 citation statements)

References 22 publications

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“…Previous studies showed that CYP2E1 could synergize and increase the susceptibility of hepatic cells to different chemicals (18,19). Overexpression of CYP2E1 could enhance sensitivity of hepG2 cells to fas-mediated cytotoxicity (31). In the present study, we also showed that CYP2E1 inhibition attenuated the synergetic effect of VK2 and EtOH in Smmc-7721 cells.…”

Section: Discussionsupporting

confidence: 75%

Cytochrome P450 2E1 increases the sensitivity of hepatoma cells to vitamin K2

Wang

Song

et al. 2017

International Journal of Oncology

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Although vitamin K2 (VK2) exhibits inhibitory effects on the viability of hepatoma cells, hepatoma cells are insensitive to VK2. Therefore, this investigation is an attempt to enhance the sensitivity of hepatoma cells to VK2. Our results showed that VK2 acted synergistically with ethanol (EtOH) to inhibit the viability of Smmc-7721 cells, mainly because cytochrome P450 2E1 (CYP2E1) was activated by EtOH. The synergistic effect of VK2 and EtOH was also observed in QGY-7703 cells, which also express CYP2E1. However, in HepG2 cells, which do not express CYP2E1, the synergistic effect of VK2 and EtOH was not observed. In addition, we demonstrated that CYP2E1 could be induced by VK2 via both post-transcriptional and transcriptional mechanisms. These results suggest that induction of CYP2E1 can enhance the inhibitory effect of VK2 on the viability of hepatoma cells. CYP2E1 may be an attractive target for enhanced antitumor effects of VK2 in hepatocellular carcinoma treatment.

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Section: Discussionsupporting

confidence: 75%

Cytochrome P450 2E1 increases the sensitivity of hepatoma cells to vitamin K2

Wang

Song

et al. 2017

International Journal of Oncology

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“…The c2 allele enhanced the ability of CYP2E1 as a principal P-450 responsible for the metabolism of ethanol and a major component of the microsomal ethanol-oxidizing system because ethanol exerts its carcinogenic effect in the liver among others via the induction of CYP2E1 and the generation of carcinogenic etheno-DNA adducts (Lee et al, 1996;Millonig et al, 2011). CYP2E1 potentiates Fas-mediated HepG2 cells toxicity via the induction of oxidative stress to promote apoptosis, too (Yan et al, 2008). Human CYP2E1 also involved in the formation of glycidamide from acrylamide for glycidamide is suspected of being the ultimate carcinogenic metabolite of acrylamide (Settels et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

CYP2E1 RsaI/PstI Polymorphism and Liver Cancer Risk among East Asians: a Huge Review and Meta-analysis

Tian

Li²,

Zhao³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Published data on any association between the CYP2E1 RsaI/PstI (c1/c2) polymorphism and liver cancer risk among east Asians are inconclusive. The aim of this Human Genome Epidemiology (HuGE) review and metaanalysis was to derive a more precise estimation of the relationship. A literature search of Pubmed, Embase, Web of science and CBM databases from inception through July 2012 was conducted. Twelve case-control studies were included with a total of 1,552 liver cancer cases and 1,763 healthy controls. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association under five genetic models. When all the eligible studies were pooled into the meta-analysis, the results showed that the c2 allele and the c2 carrier (c2/c2 + c2/c1) of RsaI/PstI polymorphism were associated with decreased risk of liver cancer among east Asians (

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“…The observed cytotoxicity was clearly dependent on the concentration of acetaminophen and the amount of CYP2E1 adenovirus (multiplicity of infection, moi). HepG2 cells infected with CYP2E1 adenovirus have also been used to study the role of CYP2E1 in Fas-mediated cytotoxicity, oxidative stress and apoptosis (Yan et al 2008). Vignati et al (2005) proposed HepG2 cells transiently transfected with CYP3A4 as an in vitro tool for metabolism-mediated toxicity screenings.…”

Section: Alternative Models To Primary Human Hepatocytesmentioning

confidence: 99%

Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME

Hewitt²,

et al. 2013

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This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4α, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4α), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell–derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-013-1078-5) contains supplementary material, which is available to authorized users.

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Overexpression of CYP2E1 enhances sensitivity of HepG2 cells to Fas-mediated cytotoxicity

Cited by 8 publications

References 22 publications

Cytochrome P450 2E1 increases the sensitivity of hepatoma cells to vitamin K2

Cytochrome P450 2E1 increases the sensitivity of hepatoma cells to vitamin K2

CYP2E1 RsaI/PstI Polymorphism and Liver Cancer Risk among East Asians: a Huge Review and Meta-analysis

Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME

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