Regulation of Cytochrome P450 2e1 Expression by Ethanol: Role of Oxidative Stress-mediated Pkc/jnk/sp1 Pathway

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2013 Mar 23

PMID 23519123

Citations 82

Authors

M Jin

A Ande

A Kumar

S Kumar

Affiliations

Soon will be listed here.

Abstract

CYP2E1 metabolizes ethanol leading to production of reactive oxygen species (ROS) and acetaldehyde, which are known to cause not only liver damage but also toxicity to other organs. However, the signaling pathways involved in CYP2E1 regulation by ethanol are not clear, especially in extra-hepatic cells. This study was designed to examine the role of CYP2E1 in ethanol-mediated oxidative stress and cytotoxicity, as well as signaling pathways by which ethanol regulates CYP2E1 in extra-hepatic cells. In this study, we used astrocytic and monocytic cell lines, because they are important cells in central nervous system . Our results showed that 100 mM ethanol significantly induced oxidative stress, apoptosis, and cell death at 24 h in the SVGA astrocytic cell line, which was rescued by a CYP2E1 selective inhibitor, diallyl sulfide (DAS), CYP2E1 siRNA, and antioxidants (vitamins C and E). Further, we showed that DAS and vitamin C abrogated ethanol-mediated (50 mM) induction of CYP2E1 at 6 h, as well as production of ROS at 2 h, suggesting the role of oxidative stress in ethanol-mediated induction of CYP2E1. We then investigated the role of the protein kinase C/c-Jun N-terminal kinase/specificity protein1 (PKC/JNK/SP1) pathway in oxidative stress-mediated CYP2E1 induction. Our results showed that staurosporine, a non-specific inhibitor of PKC, as well as specific PKCζ inhibitor and PKCζ siRNA, abolished ethanol-induced CYP2E1 expression. In addition, inhibitors of JNK (SP600125) and SP1 (mithramycin A) completely abrogated induction of CYP2E1 by ethanol in SVGA astrocytes. Subsequently, we showed that CYP2E1 is also responsible for ethanol-mediated oxidative stress and apoptotic cell death in U937 monocytic cell lines. Finally, our results showed that PKC/JNK/SP1 pathway is also involved in regulation of CYP2E1 in U937 cells. This study has clinical implications with respect to alcohol-associated neuroinflammatory toxicity among alcohol users.

Citing Articles

New insights in the pathogenesis of alcohol-related liver disease: The metabolic, immunologic, and neurologic pathways.

Ryu T, Kim K, Choi S, Chung K, Jeong W Liver Res. 2025; 7(1):1-8.

PMID: 39959703 PMC: 11791844. DOI: 10.1016/j.livres.2022.09.004.

Molecular Regulation of Palatogenesis and Clefting: An Integrative Analysis of Genetic, Epigenetic Networks, and Environmental Interactions.

Im H, Song Y, Kim J, Park D, Kim D, Kim H Int J Mol Sci. 2025; 26(3).

PMID: 39941150 PMC: 11818578. DOI: 10.3390/ijms26031382.

Targeting tRNA-Derived Non-Coding RNA Alleviates Diabetes-Induced Visual Impairment through Protecting Retinal Neurovascular Unit.

Yao J, Yao W, Zhu J, Liu Y, Liu J, Ji Y Adv Sci (Weinh). 2024; 12(1):e2411042.

PMID: 39513253 PMC: 11714213. DOI: 10.1002/advs.202411042.

Hepatocyte-Targeted Lipid Nanoparticle Delivery of HERC2 Plasmid Controls Drug-Induced Hepatotoxicity by Limiting β-Catenin-Regulated CYP2E1 Expression.

Liu Y, Xu Q, Liu Y, Cao S, Luo J, Zheng Z Adv Sci (Weinh). 2024; 11(46):e2401633.

PMID: 39440550 PMC: 11633468. DOI: 10.1002/advs.202401633.

Curcumin attenuates smoking and drinking activated NF-κB/IL-6 inflammatory signaling axis in cervical cancer.

Kashyap V, Nagesh P, Singh A, Massey A, Darkwah G, George A Cancer Cell Int. 2024; 24(1):343.

PMID: 39428480 PMC: 11492755. DOI: 10.1186/s12935-024-03513-z.

References

Wang K, Brems J, Gamelli R, Holterman A . C/EBPα and C/EBPβ binding proteins modulate hepatocyte apoptosis through iNOS signaling pathway. Biochim Biophys Acta. 2011; 1813(8):1395-403. DOI: 10.1016/j.bbamcr.2011.04.004. View

Wang X, Cederbaum A . Acute ethanol pretreatment increases FAS-mediated liver injury in mice: role of oxidative stress and CYP2E1-dependent and -independent pathways. Free Radic Biol Med. 2007; 42(7):971-84. PMC: 1914038. DOI: 10.1016/j.freeradbiomed.2006.12.023. View

Dupont I, Lucas D, Clot P, Menez C, Albano E . Cytochrome P4502E1 inducibility and hydroxyethyl radical formation among alcoholics. J Hepatol. 1998; 28(4):564-71. DOI: 10.1016/s0168-8278(98)80279-1. View

Zhai Q, Lu S, Lin Y, Yang Q, Yu B . Oxidative stress potentiated by diallylsulfide, a selective CYP2E1 inhibitor, in isoniazid toxic effect on rat primary hepatocytes. Toxicol Lett. 2008; 183(1-3):95-8. DOI: 10.1016/j.toxlet.2008.10.007. View

Cederbaum A . Nrf2 and antioxidant defense against CYP2E1 toxicity. Expert Opin Drug Metab Toxicol. 2009; 5(10):1223-44. DOI: 10.1517/17425250903143769. View

Prandota J . Important role of proinflammatory cytokines/other endogenous substances in drug-induced hepatotoxicity: depression of drug metabolism during infections/inflammation states, and genetic polymorphisms of drug-metabolizing enzymes/cytokines may.... Am J Ther. 2005; 12(3):254-61. View

Kelicen P, Tindberg N . Lipopolysaccharide induces CYP2E1 in astrocytes through MAP kinase kinase-3 and C/EBPbeta and -delta. J Biol Chem. 2003; 279(16):15734-42. DOI: 10.1074/jbc.M311850200. View

Takahashi T, Lasker J, Rosman A, Lieber C . Induction of cytochrome P-4502E1 in the human liver by ethanol is caused by a corresponding increase in encoding messenger RNA. Hepatology. 1993; 17(2):236-45. View

Suzuki Y, Ando F, Ohsawa I, Shimokata H, Ohta S . Association of alcohol dehydrogenase 2*1 allele with liver damage and insulin concentration in the Japanese. J Hum Genet. 2005; 51(1):31-37. DOI: 10.1007/s10038-005-0318-9. View

10.

Viaggi C, Vaglini F, Pardini C, Caramelli A, Corsini G . MPTP-induced model of Parkinson's disease in cytochrome P450 2E1 knockout mice. Neuropharmacology. 2009; 56(8):1075-81. DOI: 10.1016/j.neuropharm.2009.03.003. View

11.

Abdel-Razzak Z, Garlatti M, Aggerbeck M, Barouki R . Determination of interleukin-4-responsive region in the human cytochrome P450 2E1 gene promoter. Biochem Pharmacol. 2004; 68(7):1371-81. DOI: 10.1016/j.bcp.2004.06.003. View

12.

Gopalakrishna R, Gundimeda U . Antioxidant regulation of protein kinase C in cancer prevention. J Nutr. 2002; 132(12):3819S-3823S. DOI: 10.1093/jn/132.12.3819S. View

13.

Szuster-Ciesielska A, Mizerska-Dudka M, Daniluk J, Kandefer-Szerszen M . Butein inhibits ethanol-induced activation of liver stellate cells through TGF-β, NFκB, p38, and JNK signaling pathways and inhibition of oxidative stress. J Gastroenterol. 2012; 48(2):222-37. PMC: 3575555. DOI: 10.1007/s00535-012-0619-7. View

14.

Lieber C . The discovery of the microsomal ethanol oxidizing system and its physiologic and pathologic role. Drug Metab Rev. 2004; 36(3-4):511-29. DOI: 10.1081/dmr-200033441. View

15.

Bai J, Cederbaum A . Overexpression of CYP2E1 in mitochondria sensitizes HepG2 cells to the toxicity caused by depletion of glutathione. J Biol Chem. 2005; 281(8):5128-36. DOI: 10.1074/jbc.M510484200. View

16.

Haorah J, Heilman D, Knipe B, Chrastil J, Leibhart J, Ghorpade A . Ethanol-induced activation of myosin light chain kinase leads to dysfunction of tight junctions and blood-brain barrier compromise. Alcohol Clin Exp Res. 2005; 29(6):999-1009. DOI: 10.1097/01.alc.0000166944.79914.0a. View

17.

Crews F, Bechara R, Brown L, Guidot D, Mandrekar P, Oak S . Cytokines and alcohol. Alcohol Clin Exp Res. 2006; 30(4):720-30. DOI: 10.1111/j.1530-0277.2006.00084.x. View

18.

Ben Achour S, Pascual O . Astrocyte-neuron communication: functional consequences. Neurochem Res. 2012; 37(11):2464-73. DOI: 10.1007/s11064-012-0807-0. View

19.

Lu Y, Cederbaum A . CYP2E1 and oxidative liver injury by alcohol. Free Radic Biol Med. 2007; 44(5):723-38. PMC: 2268632. DOI: 10.1016/j.freeradbiomed.2007.11.004. View

20.

Tsutsumi M, Lasker J, Takahashi T, Lieber C . In vivo induction of hepatic P4502E1 by ethanol: role of increased enzyme synthesis. Arch Biochem Biophys. 1993; 304(1):209-18. DOI: 10.1006/abbi.1993.1341. View