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 hepatotox-icity, 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-adminis-tered 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 sphingomyeli-nases, 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.
Article PDF
Similar content being viewed by others
Explore related subjects
Discover the latest articles, news and stories from top researchers in related subjects.Avoid common mistakes on your manuscript.
References
Adinehzadeh, M. and Reo, N.V. (1998). Effects of peroxisome proliferators on rat liver phospholipids: sphingomyelin degradation may be involved in hepatotoxic mechanism of perfluorode-canoic acid. Chem. Res. Toxicol., 11, 428–440.
Bligh, E.G. and Dyer, W.J. (1959). A rapid method of total lipid extraction and purification. Can. J. Biochem. Physiol., 37, 911–917.
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 phos-phatase-1. J. Biol. Chem., 277, 12587–12595.
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.
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.
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 sphingoyelinase. J. Biol. Chem., 273, 7560–7565.
Cuvillier, O. (2002). Sphingosine in apoptosis signaling. Biochim. Biophys. Acta, 1585, 153–162.
Dzhekova-Stojkova, S., Bogdanska, J. and Stojkova, Z. (2001). Peroxisome proliferators: their biological and toxicological effects. Clin. Chem. Lab. Med., 39, 468–474.
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.
Hannun, Y.A. (1996). Functions of ceramide in coordinating cellular responses to stress. Science, 274, 1855–1859.
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.
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-ethyl-hexyl) phthalate. Reprod. Toxicol., 16, 529–653.
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.
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.
Liu, B. and Hannun, Y.A. (2000). Sphingomyelinase assay using radiolabeled substrate. Methods. Enzymol., 311, 164–167.
Luberto, C. and Hannun, Y.A. (1998). Sphingomyelin synthase, a potential regulator of intracellular levels of ceramide and dia-cylglycerol during SV40 transformation. Does sphingomyelin synthase account for the putative phosphatidylcholine-specific phospholipase C? J. Biol. Chem., 273, 14550–14559.
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.
Nikolova-Karakashian, M. and Merrill, A.H., Jr. (2000). Cerami-dases. Methods Enzymol., 311, 194–201.
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 proliferators-activated receptor-gamma and ERK 1/2 activation in testis of Sprague-Dawley rats. J. Toxicol. Environ. Health A, 70, 1296–1303.
Spiegel, S., Foster, D. and Kolesnick, R. (1996). Signal transducion through lipid second messengers. Curr. Opin. Cell Biol., 8, 159–167.
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.
Xu, Y., Agrawal, S., Cook, T.J. and Knipp, G.T. (2007). Di-(2-eth-ylhexyl)-phthalate affects lipid profiling in fetal rat brain upon maternal exposure. Arch. Toxicol., 81, 57–62.
Xu, Y., Cook, T.J. and Knipp, G.T. (2005). Effects of di-(2-ethyl-hexyl)-phthalate (DEHP) and its metabolites on fatty acid homeostasis regulating proteins in rat placental HRP-1 trophoblast cells. Toxicol. Sci., 84, 287–300.
Xu, Y., Knipp, G.T. and Cook, T.J. (2006). Effects of di-(2-ethyl-hexyl)-phthalate and its metabolites on the lipid profiling in rat HRP-1 trophoblast cells. Arch. Toxicol., 80, 293–298.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Jo, JY., Kim, TH., Jeong, HY. et al. Effect of Di-(2-ethylhexyl)-phthalate on Sphingolipid Metabolic Enzymes in Rat Liver. Toxicol Res. 27, 185–190 (2011). https://doi.org/10.5487/TR.2011.27.3.185
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.5487/TR.2011.27.3.185