Skip to main content
Log in

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

  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price includes VAT (France)

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

BaP:

benzo[a]pyrene

CYP or CYP450:

cytochrome P450 family

CYP1A1:

cytochrome P450 1A1

HepG2 cells:

human hepatoma cells

HNE:

hydroxynonenal

MDA:

malondialdehyde

NAFLD:

nonalcoholic fatty liver disease

OA:

oleic acid

ROS:

reactive oxygen species

siRNA:

small interfering RNA

SOD:

superoxide dismutase

TAG:

triacylglyceride

References

  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.

    Article  PubMed  CAS  Google Scholar 

  2. Clark, J. M., and Diehl, A. M. (2003) Nonalcoholic fatty liver disease: an underrecognized cause of cryptogenic cir-rhosis, JAMA, 289, 3000–3004.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Angulo, P. (2002) Nonalcoholic fatty liver disease, N. Engl. J. Med., 346, 1221–1231.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  6. Pessayre, D., Berson, A., Fromenty, B., and Mansouri, A. (2001) Mitochondria in steatohepatitis, Semin. Liver Dis., 21, 57–69.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  9. Myasoedova, K. N. (2008) New findings in studies of cytochromes P450, Biochemistry (Moscow), 73, 965–969.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  13. Stohs, S. J. (1990) Oxidative stress induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), Free Radic. Biol. Med., 9, 79–90.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  19. Liu, J., Sridhar, J., and Foroozesh, M. (2013) Cytochrome P450 family 1 inhibitors and structure-activity relation-ships, Molecules, 18, 14470–14495.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  22. Ganesh, S., and Rustgi, V. K. (2016) Current pharmaco-logic therapy for nonalcoholic fatty liver disease, Clin. Liver Dis., 20, 351–364.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  36. Scott, E. E. (2016) The role of protein–protein and pro-tein–membrane interactions on P450 function, Drug Metab. Dispos., 44, 576–590.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Y. Jin.

Additional information

Originally published in Biochemistry (Moscow) On-Line Papers in Press, as Manuscript BM17-379, March 12, 2018.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Huang, B., Bao, J., Cao, YR. et al. Cytochrome P450 1A1 (CYP1A1) Catalyzes Lipid Peroxidation of Oleic Acid-Induced HepG2 Cells. Biochemistry Moscow 83, 595–602 (2018). https://doi.org/10.1134/S0006297918050127

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0006297918050127

Keywords

Navigation