Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
권호 표지
DOI QR코드

DOI QR Code

Effect of Di-(2-ethylhexyl)-phthalate on Sphingolipid Metabolic Enzymes in Rat Liver

  • Jo, Ji-Yeong (Laboratories of Pharmacology, College of Pharmacy (BK21 Project) and Longevity Life Science and Technology Institutes, Pusan National University) ;
  • Kim, Tae-Hyung (Laboratories of Molecular Toxicology, College of Pharmacy (BK21 Project) and Longevity Life Science and Technology Institutes, Pusan National University) ;
  • Jeong, Hye-Young (Laboratories of Pharmacology, College of Pharmacy (BK21 Project) and Longevity Life Science and Technology Institutes, Pusan National University) ;
  • Lim, Sung-Mee (Department of Food Science & Technology, Tongmyong University) ;
  • Kim, Hyung-Sik (Laboratories of Molecular Toxicology, College of Pharmacy (BK21 Project) and Longevity Life Science and Technology Institutes, Pusan National University) ;
  • Im, Dong-Soon (Laboratories of Pharmacology, College of Pharmacy (BK21 Project) and Longevity Life Science and Technology Institutes, Pusan National University)
  • Received : 2011.04.07
  • Accepted : 2011.08.11
  • Published : 2011.09.01
Download PDF
⟨ Previous Next ⟩

Abstract

Di-(2-ethylhexyl)-phthalate (DEHP), the most widely utilized industrial plastizer and a ubiquitous environmental contaminant, can act on peroxisome proliferators-activated nuclear hormone receptor family (PPAR) isoforms. To understand the contribution of sphingolipid metabolism to DEHP-induced hepatotoxicity, effect of DEHP exposure on activities of sphingolipid metabolic enzymes in rat liver was investigated. DEHP (250, 500 or 750 mg/kg) was administered to the rats through oral gavage daily for 28 days. The activities of acidic and alkaline ceramidases were slightly increased in 250 mg/kg DEHP-administered rat livers and significantly elevated in 500 mg/kg DEHP-administered ones, although the level of 750 mg/kg DEHP-administered ones was not increased. Neutral ceramidase, acidic and neutral sphingomyelinases, sphingomyeline synthase and ceramide syhthase were not changed at all by DEHP exposure. Therefore, acidic and alkaline ceramidases might play important roles in DEHP-induced hepatotoxicity.

Keywords

References

  1. Adinehzadeh, M. and Reo, N.V. (1998). Effects of peroxisome proliferators on rat liver phospholipids: sphingomyelin degradation may be involved in hepatotoxic mechanism of perfluorodecanoic acid. Chem. Res. Toxicol., 11, 428-440. https://doi.org/10.1021/tx970155t
  2. Bligh, E.G. and Dyer, W.J. (1959). A rapid method of total lipid extraction and purification. Can. J. Biochem. Physiol., 37, 911-917. https://doi.org/10.1139/o59-099
  3. Chalfant, C.E., Rathman, K., Pinkerman, R.L., Wood, R.E., Obeid, L.M., Ogretmen, B. and Hannun, Y.A. (2002). De novo ceramide regulates the alternative splicing of caspase 9 and Bcl-x in A549 lung adenocarcinoma cells. Dependence on protein phosphatase- 1. J. Biol. Chem., 277, 12587-12595. https://doi.org/10.1074/jbc.M112010200
  4. Chen, J., Nikolova-Karakashian, M., Merrill, A.H. Jr. and Morgan, E.T. (1995). Regulation of cytochrome P450 2C11 (CYP2C11) gene expression by interleukin-1, sphingomyelin hydrolysis, and ceramides in rat hepatocytes. J. Biol. Chem., 270, 25233-25238. https://doi.org/10.1074/jbc.270.42.25233
  5. Chun, Y.J., Park, S. and Yang, S.A. (2003). Activation of Fas receptor modulates cytochrome P450 3A4 expression in human colon carcinoma cells. Toxicol. Lett., 146, 75-81. https://doi.org/10.1016/j.toxlet.2003.09.002
  6. Cock, J.G., Tepper, A.D., de Vries, E., van Blitterswijk, W.J. and Borst, J. (1998). CD95 (Fas/APO-1) induces ceramide formation and apoptosis in the absence of a functional acid sphingomyelinase. J. Biol. Chem., 273, 7560-7565. https://doi.org/10.1074/jbc.273.13.7560
  7. Cuvillier, O. (2002). Sphingosine in apoptosis signaling. Biochim. Biophys. Acta, 1585, 153-162. https://doi.org/10.1016/S1388-1981(02)00336-0
  8. Dzhekova-Stojkova, S., Bogdanska, J. and Stojkova, Z. (2001). Peroxisome proliferators: their biological and toxicological effects. Clin. Chem. Lab. Med., 39, 468-474. https://doi.org/10.1515/CCLM.2001.076
  9. Futerman, A.H., Stieger, B., Hubbard, A.L. and Pagano, R.E. (1990). Sphingomyelin synthesis in rat liver occurs predominantly at the cis and medial cisternae of the Golgi apparatus. J. Biol. Chem., 265, 8650-8657.
  10. Hannun, Y.A. (1996). Functions of ceramide in coordinating cellular responses to stress. Science, 274, 1855-1859. https://doi.org/10.1126/science.274.5294.1855
  11. Igarashi, Y. and Hakomori, S. (1989). Enzymatic synthesis of N,N-dimethyl-sphingosine: demonstration of the sphingosine: N-methyltransferase in mouse brain. Biochem. Biophys. Res. Commun., 164, 1411-1416. https://doi.org/10.1016/0006-291X(89)91827-5
  12. Kavlock, R., Boekelheide, K., Chapin, R., Cunningham, M., Faustman, E., Foster, P., Golub, M., Henderson, R., Hinberg, I., Little, R., Seed, J., Shea, K., Tabacova, S., Tyl, R., Williams, P. and Zacharewski, T. (2002). NTP Center for the Evaluation of Risks to Human Reproduction: phthalates expert panel report on the reproductive and developmental toxicity of di(2-ethylhexyl) phthalate. Reprod. Toxicol., 16, 529-653. https://doi.org/10.1016/S0890-6238(02)00032-1
  13. Kim, N.Y., Kim, T.H., Lee, E., Patra, N., Lee, J., Shin, M.O., Kwack, S.J., Park, K.L., Han, S.Y., Kang, T.S., Kim, S.H., Lee, B.M. and Kim, H.S. (2010). Functional role of phospholipase D (PLD) in di(2-ethylhexyl) phthalate-induced hepatotoxicity in Sprague-Dawley rats. J. Toxicol. Environ. Health A, 73, 1560-1569. https://doi.org/10.1080/15287394.2010.511582
  14. Lightle, S.A., Oakley, J.I. and Nikolova-Karakashian, M.N. (2000). Activation of sphingolipid turnover and chronic generation of ceramide and sphingosine in liver during aging. Mech. Ageing Dev., 120, 111-125. https://doi.org/10.1016/S0047-6374(00)00191-3
  15. Liu, B. and Hannun, Y.A. (2000). Sphingomyelinase assay using radiolabeled substrate. Methods. Enzymol., 311, 164-167. https://doi.org/10.1016/S0076-6879(00)11077-8
  16. Luberto, C. and Hannun, Y.A. (1998). Sphingomyelin synthase, a potential regulator of intracellular levels of ceramide and diacylglycerol during SV40 transformation. Does sphingomyelin synthase account for the putative phosphatidylcholine-specific phospholipase C? J. Biol. Chem., 273, 14550-14559. https://doi.org/10.1074/jbc.273.23.14550
  17. Morell, P. and Radin, N.S. (1970). Specificity in ceramide biosynthesis from long chain bases and various fatty acyl coenzyme A's by brain microsomes. J. Biol. Chem., 245, 342-350.
  18. Nikolova-Karakashian, M. and Merrill, A.H., Jr. (2000). Ceramidases. Methods Enzymol., 311, 194-201. https://doi.org/10.1016/S0076-6879(00)11081-X
  19. Ryu, J.Y., Whang, J., Park, H., Im, J.Y., Kim, J., Ahn, M.Y., Lee, J., Kim, H.S., Lee, B.M., Yoo, S.D., Kwack, S.J., Oh, J.H., Park, K.L., Han, S.Y. and Kim, S.H. (2007). Di(2-ethylhexyl) phthalate induces apoptosis through peroxisome proliferatorsactivated receptor-gamma and ERK 1/2 activation in testis of Sprague-Dawley rats. J. Toxicol. Environ. Health A, 70, 1296-1303. https://doi.org/10.1080/15287390701432160
  20. Spiegel, S., Foster, D. and Kolesnick, R. (1996). Signal transduction through lipid second messengers. Curr. Opin. Cell Biol., 8, 159-167. https://doi.org/10.1016/S0955-0674(96)80061-5
  21. Strelow, A., Bernardo, K., Adam-Klages, S., Linke, T., Sandhoff, K., Kronke, M. and Adam, D. (2000). Overexpression of acid ceramidase protects from tumor necrosis factor-induced cell death. J. Exp. Med., 192, 601-612. https://doi.org/10.1084/jem.192.5.601
  22. Xu, Y., Agrawal, S., Cook, T.J. and Knipp, G.T. (2007). Di-(2-ethylhexyl)-phthalate affects lipid profiling in fetal rat brain upon maternal exposure. Arch. Toxicol., 81, 57-62. https://doi.org/10.1007/s00204-006-0143-8
  23. Xu, Y., Cook, T.J. and Knipp, G.T. (2005). Effects of di-(2-ethylhexyl)-phthalate (DEHP) and its metabolites on fatty acid homeostasis regulating proteins in rat placental HRP-1 trophoblast cells. Toxicol. Sci., 84, 287-300. https://doi.org/10.1093/toxsci/kfi083
  24. Xu, Y., Knipp, G.T. and Cook, T.J. (2006). Effects of di-(2-ethylhexyl)-phthalate and its metabolites on the lipid profiling in rat HRP-1 trophoblast cells. Arch. Toxicol., 80, 293-298. https://doi.org/10.1007/s00204-005-0047-z