Biochemistry (Moscow)

, Volume 83, Issue 5, pp 595–602 | Cite as

Cytochrome P450 1A1 (CYP1A1) Catalyzes Lipid Peroxidation of Oleic Acid-Induced HepG2 Cells

  • B. Huang
  • J. Bao
  • Y.-R. Cao
  • H.-F. Gao
  • Y. JinEmail author


Nonalcoholic fatty liver disease (NAFLD) is a chronic hepatic disease associated with excessive accumulation of lipids in hepatocytes. As the disease progresses, oxidative stress plays a pivotal role in the development of hepatic lipid peroxidation. Cytochrome P450 1A1 (CYP1A1), a subtype of the cytochrome P450 family, has been shown to be a vital modulator in production of reactive oxygen species. However, the exact role of CYP1A1 in NAFLD is still unclear. The aim of this study was to investigate the effects of CYP1A1 on lipid peroxidation in oleic acid (OA)-treated human hepatoma cells (HepG2). We found that the expression of CYP1A1 is elevated in OA-stimulated HepG2 cells. The results of siRNA transfection analysis indicated that CYP1A1-siRNA inhibited the lipid peroxidation in OA-treated HepG2 cells. Additionally, compared with siRNA-transfected and benzo[a]pyrene (BaP)-OA-induced HepG2 cells, overexpression of CYP1A1 by BaP further accelerated the lipid peroxidation in OA-treated HepG2 cells. These observations reveal a regulatory role of CYP1A1 in liver lipid peroxidation and imply CYP1A1 as a potential therapeutic target.


nonalcoholic fatty liver disease (NAFLD) CYP1A1 CYP1A1-siRNA oxidative stress lipid peroxidation 




CYP or CYP450

cytochrome P450 family


cytochrome P450 1A1

HepG2 cells

human hepatoma cells






nonalcoholic fatty liver disease


oleic acid


reactive oxygen species


small interfering RNA


superoxide dismutase




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  1. 1.
    Xu, C., Wang, G., Hao, Y., Zhi, J., Zhang, L., and Chang, C. (2011) Correlation analysis between gene expression profile of rat liver tissues and high-fat emulsion-induced nonalcoholic fatty liver, Dig. Dis. Sci., 56, 2299–2308.CrossRefPubMedGoogle Scholar
  2. 2.
    Clark, J. M., and Diehl, A. M. (2003) Nonalcoholic fatty liver disease: an underrecognized cause of cryptogenic cir-rhosis, JAMA, 289, 3000–3004.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Wong, C. R., Nguyen, M. H., and Lim, J. K. (2016) Hepatocellular carcinoma in patients with non-alcoholic fatty liver disease, World J. Gastroenterol., 22, 8294–8303.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Angulo, P. (2002) Nonalcoholic fatty liver disease, N. Engl. J. Med., 346, 1221–1231.CrossRefPubMedGoogle Scholar
  5. 5.
    Petrosillo, G., Portincasa, P., Grattagliano, I., Casanova, G., Matera, M., Ruggiero, F. M., Ferri, D., and Paradies, G. (2007) Mitochondrial dysfunction in rat with nonalcoholic fatty liver involvement of complex I, reactive oxygen species and cardiolipin, Biochim. Biophys. Acta, 1767, 1260–1267.CrossRefPubMedGoogle Scholar
  6. 6.
    Pessayre, D., Berson, A., Fromenty, B., and Mansouri, A. (2001) Mitochondria in steatohepatitis, Semin. Liver Dis., 21, 57–69.CrossRefPubMedGoogle Scholar
  7. 7.
    Esterbauer, H., Schaur, R. J., and Zollner, H. (1991) Chemistry and biochemistry of 4-hydroxynonenal, malon-aldehyde and related aldehydes, Free Radic. Biol. Med., 11, 81–128.CrossRefPubMedGoogle Scholar
  8. 8.
    Rolo, A. P., Teodoro, J. S., and Palmeira, C. M. (2012) Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis, Free Radic. Biol. Med., 52, 59–69.CrossRefPubMedGoogle Scholar
  9. 9.
    Myasoedova, K. N. (2008) New findings in studies of cytochromes P450, Biochemistry (Moscow), 73, 965–969.CrossRefGoogle Scholar
  10. 10.
    Bonina, T. A., Gilep, A. A., Estabrook, R. W., and Usanov, S. A. (2005) Engineering of proteolytically stable NADPH-cytochrome P450 reductase, Biochemistry (Moscow), 70, 357–365.CrossRefGoogle Scholar
  11. 11.
    Fer, M., Corcos, L., Dreano, Y., Plee-Gautier, E., Salaun, J. P., Berthou, F., and Amet, Y. (2008) Cytochromes P450 from family 4 are the main omega hydroxylating enzymes in humans: CYP4F3B is the prominent player in PUFA metabolism, J. Lipid Res., 49, 2379–2389.CrossRefPubMedGoogle Scholar
  12. 12.
    Puntarulo, S., and Cederbaum, A. I. (1998) Production of reactive oxygen species by microsomes enriched in specific human cytochrome P450 enzymes, Free Radic. Biol. Med., 24, 1324–1330.CrossRefPubMedGoogle Scholar
  13. 13.
    Stohs, S. J. (1990) Oxidative stress induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), Free Radic. Biol. Med., 9, 79–90.CrossRefPubMedGoogle Scholar
  14. 14.
    Melchini, A., Catania, S., Stancanelli, R., Tommasini, S., and Costa, C. (2011) Interaction of a functionalized com-plex of the flavonoid hesperetin with the AhR pathway and CYP1A1 expression: involvement in its protective effects against benzo[a]pyrene-induced oxidative stress in human skin, Cell Biol. Toxicol., 27, 371–379.CrossRefPubMedGoogle Scholar
  15. 15.
    Furue, M., Uchi, H., Mitoma, C., Hashimoto-Hachiya, A., Chiba, T., Ito, T., Nakahara, T., and Tsuji, G. (2017) Antioxidants for healthy skin: the emerging role of aryl hydrocarbon receptors and nuclear factor-erythroid 2-related factor-2, Nutrients, 9, 223.CrossRefPubMedCentralGoogle Scholar
  16. 16.
    Al-Dhfyan, A., Alhoshani, A., and Korashy, H. M. (2017) Aryl hydrocarbon receptor/cytochrome P450 1A1 pathway medi-ates breast cancer stem cells expansion through PTEN inhibi-tion and beta-catenin and Akt activation, Mol. Cancer, 16, 14.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Zou, J. G., Ma, Y. T., Xie, X., Yang, Y. N., Pan, S., Adi, D., Liu, F., and Chen, B. D. (2014) The association between CYP1A1 genetic polymorphisms and coronary artery disease in the Uygur and Han of China, Lipids Health Dis., 13, 145.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Yen, J. H., Tsai, W. C., Lin, C. H., Ou, T. T., Hu, C. J., and Liu, H. W. (2003) Cytochrome P450 1A1 and manganese superoxide dismutase genes polymorphisms in reactive arthritis, Immunol. Lett., 90, 151–154.CrossRefPubMedGoogle Scholar
  19. 19.
    Liu, J., Sridhar, J., and Foroozesh, M. (2013) Cytochrome P450 family 1 inhibitors and structure-activity relation-ships, Molecules, 18, 14470–14495.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Chiba, T., Noji, K., Shinozaki, S., Suzuki, S., Umegaki, K., and Shimokado, K. (2016) Diet-induced non-alcoholic fatty liver disease affects expression of major cytochrome P450 genes in a mouse model, J. Pharm. Pharmacol., 68, 1567–1576.CrossRefPubMedGoogle Scholar
  21. 21.
    Suzuki, S., Sato, Y., Umegaki, K., and Chiba, T. (2015) The major cytochrome P450 subtype activities in diet-induced non-alcoholic steatohepatitis mouse model, Endocrinol. Metab. Synd., 4, 190.CrossRefGoogle Scholar
  22. 22.
    Ganesh, S., and Rustgi, V. K. (2016) Current pharmaco-logic therapy for nonalcoholic fatty liver disease, Clin. Liver Dis., 20, 351–364.CrossRefPubMedGoogle Scholar
  23. 23.
    Hwang, Y. J., Wi, H. R., Kim, H. R., Park, K. W., and Hwang, K. A. (2014) Pinus densiflora Sieb. et Zucc. allevi-ates lipogenesis and oxidative stress during oleic acid-induced steatosis in HepG2 cells, Nutrients, 6, 2956–2972.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Burczynski, M. E., and Penning, T. M. (2000) Genotoxic poly-cyclic aromatic hydrocarbon ortho-quinones generated by aldo-keto reductases induce CYP1A1 via nuclear translocation of the aryl hydrocarbon receptor, Cancer Res., 60, 908–915.PubMedGoogle Scholar
  25. 25.
    An, J., Yin, L. L., Shang, Y., Zhong, Y. F., Zhang, X. Y., Wu, M. H., Yu, Z. Q., Sheng, G. Y., Fu, J. M., and Huang, Y. C. (2011) The combined effects of BDE47 and BaP on oxidative-ly generated DNA damage in L02 cells and the possible molec-ular mechanism, Mutat Res. Gen. Tox. En., 721, 192–198.CrossRefGoogle Scholar
  26. 26.
    Xie, C., Chen, Z., Zhang, C., Xu, X., Jin, J., Zhan, W., Han, T., and Wang, J. (2016) Dihydromyricetin ameliorates oleic acid-induced lipid accumulation in L02 and HepG2 cells by inhibit-ing lipogenesis and oxidative stress, Life Sci., 157, 131–139.CrossRefPubMedGoogle Scholar
  27. 27.
    Charlton, M., Krishnan, A., Viker, K., Sanderson, S., Cazanave, S., McConico, A., Masuoko, H., and Gores, G. (2011) Fast food diet mouse: novel small animal model of NASH with ballooning, progressive fibrosis, and high phys-iological fidelity to the human condition, Am. J. Physiol. Gastrointest. Liver Physiol., 301, G825–834.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Chatuphonprasert, W., Udomsuk, L., Monthakantirat, O., Churikhit, Y., Putalun, W., and Jarukamjorn, K. (2013) Effects of Pueraria mirifica and miroestrol on the antioxi-dation-related enzymes in ovariectomized mice, J. Pharm. Pharmacol., 65, 447–456.CrossRefPubMedGoogle Scholar
  29. 29.
    Jarukamjorn, K., Jearapong, N., Pimson, C., and Chatuphonprasert, W. (2016) A high-fat, high-fructose diet induces antioxidant imbalance and increases the risk and progression of nonalcoholic fatty liver disease in mice, Scientifica, 2016, 5029414.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Spahis, S., Delvin, E., Borys, J. M., and Levy, E. (2017) Oxidative stress as a critical factor in nonalcoholic fatty liver disease pathogenesis, Antioxid. Redox Signal., 26, 519.CrossRefPubMedGoogle Scholar
  31. 31.
    Agbor, L. N., Walsh, M. T., Boberg, J. R., and Walker, M. K. (2012) Elevated blood pressure in cytochrome P4501A1 knock-out mice is associated with reduced vasodilation to omega-3 polyunsaturated fatty acids, Toxicol. Appl. Pharm., 264, 351–360.CrossRefGoogle Scholar
  32. 32.
    Stiborova, M., Martinek, V., Rydlova, H., Koblas, T., and Hodek, P. (2005) Expression of cytochrome P450 1A1 and its contribution to oxidation of a potential human carcino-gen 1-phenylazo-2-naphthol (Sudan I) in human livers, Cancer Lett., 220, 145–154.CrossRefPubMedGoogle Scholar
  33. 33.
    Melchini, A., Catania, S., Stancanelli, R., Tommasini, S., and Costa, C. (2011) Interaction of a functionalized com-plex of the flavonoid hesperetin with the AhR pathway and CYP1A1 expression: involvement in its protective effects against benzo[a]pyrene-induced oxidative stress in human skin, Cell Biol. Toxicol., 27, 371–379.CrossRefPubMedGoogle Scholar
  34. 34.
    Fisher, C. D., Jackson, J. P., Lickteig, A. J., Augustine, L. M., and Cherrington, N. J. (2008) Drug metabolizing enzyme induction pathways in experimental non-alcoholic steatohepatitis, Arch. Toxicol., 82, 959–964.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Barouki, R., and Morel, Y. (2001) Repression of cytochrome P450 1A1 gene expression by oxidative stress: mechanisms and biological implications, Biochem. Pharmacol., 61, 511–516.CrossRefPubMedGoogle Scholar
  36. 36.
    Scott, E. E. (2016) The role of protein–protein and pro-tein–membrane interactions on P450 function, Drug Metab. Dispos., 44, 576–590.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Go, R. E., Hwang, K. A., and Choi, K. C. (2015) Cytochrome P450 1 family and cancers, J. Steroid Biochem. Mol. Biol., 147, 24–30.CrossRefPubMedGoogle Scholar
  38. 38.
    Cherng, S. H., Lin, P., Yang, J. L., Hsu, S. L., and Lee, H. (2001) Benzo[g,h,i]perylene synergistically transactivates ben-zo[a]pyrene-induced CYP1A1 gene expression by aryl hydro-carbon receptor pathway, Toxicol. Appl. Pharmacol., 170, 63–68.CrossRefPubMedGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2018

Authors and Affiliations

  • B. Huang
    • 1
  • J. Bao
    • 1
  • Y.-R. Cao
    • 1
  • H.-F. Gao
    • 1
  • Y. Jin
    • 1
    Email author
  1. 1.Key Laboratory of Antiinflammatory and Immune Medicines, Ministry of Education, School of PharmacyAnhui Medical UniversityHefeiChina

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