Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Current Drug Metabolism
  4. Volume 25, Issue 5
  5. Article
Volume 25, Issue 5
  • ISSN: 1389-2002
  • E-ISSN: 1875-5453

Abstract

Aims

The aim of the present study is to elucidate the mechanism of CYP2E1 induction as a causative factor of Alcoholic Hepatitis (AH) and its relationship with inflammation.

Background

Chronic alcohol consumption induces CYP2E1, which is involved in the development of Alcoholic Hepatitis (AH). However, the mechanisms underlying the induction of CYP2E1 by alcohol remain unclear. Therefore, we herein investigated the induction of drug-metabolizing enzymes, particularly CYP2E1, by hydrogen peroxide (HO), the concentration of which is elevated under inflammatory conditions.

Objective

The mechanisms underlying the induction of CYP2E1 by HO were examined with a focus on Keap1, a target factor of HO.

Methods

We assessed changes in the expression of drug-metabolizing enzymes in the human hepatoma cell line, Hep3B, following treatment with HO, and evaluated changes in the expression of the NF-kB-related factor RelA(p65) after the knockdown of Keap1, a regulator of Nrf2 expression by reactive oxygen species. We also performed a promoter analysis using the upstream region of the CYP2E1 gene. We herein used the GSE89632 series for non-alcoholic hepatitis (NASH) and the GSE28619 series for AH.

Results

The induction of CYP2E1 by HO was significantly stronger than that of other drug-metabolizing enzymes. On the other hand, the knockdown of Keap1, a target of HO, markedly increased RelA(p65), an NFkB factor. Furthermore, the overexpression of RelA(p65) strongly induced the expression of CYP2E1. Four candidate p65-binding sequences were identified upstream of the CYP2E1 gene, and promoter activity assays showed that the third sequence was responsive to the overexpression of RelA(p65). We used the GSE89632 series for NASH and the GSE28619 series for AH in the present study. The expression of CYP2E1 mRNA in the liver was significantly lower in AH patients than in HC patients, but was similar in HC patients and NASH patients.

Conclusion

We herein demonstrated that the expression of CYP2E1 was induced by HO. The overexpression of RelA(p65) also induced CYP2E1 mRNA expression, whereas HO did not after the knockdown of RelA. These results suggest that HO acts on Keap1 to upregulate RelA (p65) in the NFkB system. One of the mechanisms underlying the induction of CYP2E1 was dependent on the HO-Keap1-RelA axis. The results of the database analysis revealed that the expression of CYP2E1 in the liver was significantly lower in AH patients than in NASH patients, suggesting that CYP2E1 is not the main cause of AH; however, CYP2E1 may exacerbate the pathogenesis of AH.

© 2024 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cdm/10.2174/0113892002305174240805064406
2024-08-08
2024-12-23

  • From This Site

    /content/journals/cdm/10.2174/0113892002305174240805064406
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. HonkakoskiP. NegishiM. Regulation of cytochrome P450 (CYP) genes by nuclear receptors.Biochem. J.2000347232133710.1042/bj3470321 10749660
     [Google Scholar]
  2. CederbaumA.I. Role of CYP2E1 in ethanol-induced oxidant stress, fatty liver and hepatotoxicity.Dig. Dis.201028680281110.1159/000324289 21525766
     [Google Scholar]
  3. HarjumäkiR. PridgeonC.S. Ingelman-SundbergM. CYP2E1 in alcoholic and non-alcoholic liver injury. Roles of ros, reactive intermediates and lipid overload.Int. J. Mol. Sci.20212215822110.3390/ijms22158221 34360999
     [Google Scholar]
  4. SuzukiT. YamamotoM. Molecular basis of the Keap1-Nrf2 system.Free Radic Biol Med.201588Pt B9310010.1016/j.freeradbiomed.2015.06.006
     [Google Scholar]
  5. SiswantoF.M. OguroA. AraseS. ImaokaS. WDR23 regulates the expression of Nrf2-driven drug-metabolizing enzymes.Drug Metab. Pharmacokinet.202035544145510.1016/j.dmpk.2020.06.007 32839090
     [Google Scholar]
  6. ShihV.F. TsuiR. CaldwellA. HoffmannA. A single NFκB system for both canonical and non-canonical signaling. Cell Res.20112118610210.1038/cr.2010.161
     [Google Scholar]
  7. GilmoreT.D. Introduction to NF-κB: Players, pathways, perspectives.Oncogene200625516680668410.1038/sj.onc.1209954 17072321
     [Google Scholar]
  8. HiroiT. ImaokaS. FunaeY. Dopamine formation from tyramine by CYP2D6.Biochem. Biophys. Res. Commun.1998249383884310.1006/bbrc.1998.9232
     [Google Scholar]
  9. SiswantoF.M. HandayaniM.D.N. FirmasyahR.D. OguroA. ImaokaS. Nrf2 regulates the expression of CYP2D6 by inhibiting the activity of Krüppel-Like Factor 9 (KLF9).Curr. Drug Metab.202324966768110.2174/0113892002271342231013095255 37916628
     [Google Scholar]
  10. SiswantoF.M. MitsuokaY. NakamuraM. OguroA. ImaokaS. Nrf2 and Parkin-Hsc70 regulate the expression and protein stability of p62/SQSTM1 under hypoxia.Sci. Rep.20221212126510.1038/s41598‑022‑25784‑0 36481701
     [Google Scholar]
  11. SiswantoF.M. OkukawaK. TamuraA. OguroA. ImaokaS. Hydrogen peroxide activates APE1/Ref-1 via NF-κB and Parkin: A role in liver cancer resistance to oxidative stress.Free Radic. Res.202357322323810.1080/10715762.2023.2229509 37364176
     [Google Scholar]
  12. SiswantoF.M. OguroA. ImaokaS. Sp1 is a substrate of Keap1 and regulates the activity of CRL4AWDR23 ubiquitin ligase toward Nrf2.J. Biol. Chem.202129610070410.1016/j.jbc.2021.100704 33895141
     [Google Scholar]
  13. SeitzH.K. The role of cytochrome P4502E1 in the pathogenesis of alcoholic liver disease and carcinogenesis.Chem. Biol. Interact.202031610891810.1016/j.cbi.2019.108918 31836462
     [Google Scholar]
  14. YuM. LiH. LiuQ. LiuF. TangL. LiC. YuanY. ZhanY. XuW. LiW. ChenH. GeC. WangJ. YangX. Nuclear factor p65 interacts with Keap1 to repress the Nrf2-ARE pathway.Cell. Signal.201123588389210.1016/j.cellsig.2011.01.014 21262351
     [Google Scholar]
  15. Abdel-RazzakZ. GarlattiM. AggerbeckM. BaroukiR. Determination of interleukin-4-responsive region in the human cytochrome P450 2E1 gene promoter.Biochem Pharmacol.20046871371138110.1016/j.bcp.2004.06.003 15345327
     [Google Scholar]
  16. PengH.M. CoonM.J. Promoter function and the role of cytokines in the transcriptional regulation of rabbit CYP2E1 and CYP2E2.Arch. Biochem. Biophys.2000382112913710.1006/abbi.2000.2001 11051106
     [Google Scholar]
  17. LinQ. KangX. LiX. WangT. LiuF. JiaJ. JinZ. XueY. NF-κB-mediated regulation of rat CYP2E1 by two independent signaling pathways.PLoS One20191412e022553110.1371/journal.pone.0225531 31881060
     [Google Scholar]
  18. SindhuR.K. SakaiH. OkamotoT. KikkawaY. Differential effect of interleukin-1α on rat hepatic cytochrome P450 monooxygenases.Toxicology19961141374610.1016/S0300‑483X(96)03475‑0 8931759
     [Google Scholar]
  19. AdasF. SalaünJ.P. BerthouF. PicartD. SimonB. AmetY. Requirement for ω and (ω–1)-hydroxylations of fatty acids by human cytochromes P450 2E1 and 4A11.J. Lipid Res.199940111990199710.1016/S0022‑2275(20)32422‑6 10553002
     [Google Scholar]
  20. OguroA. ImaokaS. Lysophosphatidic acids are new substrates for the phosphatase domain of soluble epoxide hydrolase.J. Lipid Res.201253350551210.1194/jlr.M022319 22217705
     [Google Scholar]
  21. GuengerichF.P. Cytochrome P450 2E1 and its roles in disease.Chem. Biol. Interact.202032210905610.1016/j.cbi.2020.109056 32198084
     [Google Scholar]
  22. KotwalP. KhajuriaP. DhimanS. KourD. DhimanS.K. KumarA. NandiU. Molecular mechanism for the involvement of CYP2E1/NF-κB axis in bedaquiline-induced hepatotoxicity.Life Sci.202331512137510.1016/j.lfs.2023.121375 36621541
     [Google Scholar]
  23. WangY. GuanS. AcharyaP. KoopD.R. LiuY. LiaoM. BurlingameA.L. CorreiaM.A. Ubiquitin-dependent proteasomal degradation of human liver cytochrome P450 2E1: Identification of sites targeted for phosphorylation and ubiquitination. J. Biol. Chem.2011286119443945610.1074/jbc.M110.176685
     [Google Scholar]
  24. MorganK. FrenchS.W. MorganT.R. Production of a cytochrome P450 2E1 transgenic mouse and initial evaluation of alcoholic liver damage.Hepatology200236112213410.1053/jhep.2002.33720 12085356
     [Google Scholar]
  25. ButuraA. NilssonK. MorganK. MorganT.R. FrenchS.W. JohanssonI. Schuppe-KoistinenI. Ingelman-SundbergM. The impact of CYP2E1 on the development of alcoholic liver disease as studied in a transgenic mouse model.J. Hepatol.200950357258310.1016/j.jhep.2008.10.020 19157621
     [Google Scholar]
  26. ImaokaS. OsadaM. MinamiyamaY. YukimuraT. ToyokuniS. TakemuraS. HiroiT. FunaeY. Role of phenobarbital-inducible cytochrome P450s as a source of active oxygen species in DNA-oxidation.Cancer Lett.2004203211712510.1016/j.canlet.2003.09.009 14732219
     [Google Scholar]
  27. MinamiyamaY. TakemuraS. ToyokuniS. ImaokaS. FunaeY. HirohashiK. YoshikawaT. OkadaS. CYP3A induction aggravates endotoxemic liver injury via reactive oxygen species in male rats.Free Radic. Biol. Med.200437570371210.1016/j.freeradbiomed.2004.05.022
     [Google Scholar]
/content/journals/cdm/10.2174/0113892002305174240805064406
Loading
Hydrogen Peroxide Induces Ethanol-inducible CYP2E1 via the NF-kB-classical Pathway: CYP2E1 mRNA Levels are not High in Alcoholic Hepatitis
Current Drug Metabolism 25, 307 (2024); https://doi.org/10.2174/0113892002305174240805064406
/content/journals/cdm/10.2174/0113892002305174240805064406
/content/journals/cdm/10.2174/0113892002305174240805064406
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s website along with the published article.

file format download Download

  • Article Type:     Research Article
Keyword(s): alcoholic hepatitis; CYP2E1; cytochrome P450; H2O2; MRNA; NF-kB

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test