Skip to main content

Advertisement

SpringerLink
Log in

Simultaneous induction of non-neoplastic and neoplastic lesions with highly proliferative hepatocytes following dietary exposure of rats to tocotrienol for 2 years

  • Genotoxicity and Carcinogenicity
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

It was recently shown that 1-year chronic exposure of rats to tocotrienol (TT) induced highly proliferative liver lesions, nodular hepatocellular hyperplasia (NHH), and independently increased the number of glutathione S-transferase placental form (GST-P)-positive hepatocytes. Focusing attention on the pathological intrinsic property of NHH, a 104-week carcinogenicity study was performed in male and female Wistar Hannover rats given TT at concentrations of 0, 0.4 or 2% in the diet. The high-dose level was adjusted to 1% in both sexes from week 51 because the survival rate of the high-dose males dropped to 42% by week 50. At necropsy, multiple cyst-like nodules were observed, as in the chronic study, but were further enlarged in size, which consequently formed a protuberant surface with a partly pedunculated shape in the liver at the high dose in both sexes. Unlike the chronic study, NHH was not always accompanied by spongiosis, and instead angiectasis was prominent in some nodules. However, several findings in the affected hepatocytes such as minimal atypia, no GST-P immunoreactivity and heterogeneous proliferation, implied that NHH did not harbor neoplastic characteristics from increased exposure despite sustained high cell proliferation. On the other hand, in the high-dose females, the incidence of hepatocellular adenomas was significantly higher than in the control. There was no TT treatment-related tumor induction in any other organs besides the liver. Thus, the overall data clearly suggested that NHH is successively enlarged by further long-term exposure to TT, but does not become neoplastic. In contrast, TT induces low levels of hepatocellular adenomas in female rats.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Agarwal MK, Agarwal ML, Gupta S (2004) Tocotrienol-rich fraction of palm oil activates p53, modulates Bax/Bcl2 ratio and induces apoptosis independent of cell cycle association. Cell Cycle 3:205–211

    PubMed  CAS  Google Scholar 

  • Bannasch P (2003) Comments on R. Karbe and R. L. Kerlin (2002). Toxicol Pathol 31:566–570

    PubMed  Google Scholar 

  • Constantinou C, Papas A, Constantinou AI (2008) Vitamin E and cancer; an insight into the anticancer activities of vitamin E isomers and analogs. Int J Cancer 123:739–752

    Article  PubMed  CAS  Google Scholar 

  • Couch JA (1991) Spongiosis hepatic: chemical induction, pathogenesis, and possible neoplastic fate in a teleost fish model. Toxicol Pathol 19:237–250

    Article  PubMed  CAS  Google Scholar 

  • Hailey JR, Walker NJ, Sells DM, Brix AE, Jokinen MP, Nyska A (2005) Classification of proliferative hepatocellular lesions in Harlan Sprague-Dawley rats chronically exposed to dioxin-like compounds. Toxicol Pathol 33:165–174

    Article  PubMed  CAS  Google Scholar 

  • Hu Z, Evarts RP, Fujio K, Marsden ER, Thorgeirsson SS (1993) Expression of hepatocyte growth factor and c-met genes during hepatic differentiation and liver development in the rat. Am J Pathol 142:1823–1830

    PubMed  CAS  Google Scholar 

  • Ito N, Tsuda H, Tatematsu M, Inoue T, Tagawa Y, Aoki T, Uwagawa S, Kagawa M, Ogiso T, Masui T, Imaida K, Fukushima S, Asamoto M (1988) Enhancing effects of various hepatocarcinogens on induction of preneoplastic glutathione S-transferase placental form positive foci in rats/an approach for a new medium-term bioassay system. Carcinogenesis 9:387–394

    Article  PubMed  CAS  Google Scholar 

  • Ito N, Imaida K, Asamoto M, Shirai T (2000) Early detection of carcinogenic substances and modifiers in rats. Mutat Res 462:209–217

    Article  PubMed  CAS  Google Scholar 

  • Karbe E, Kerlin RL (2002) Cystic degeneration/spongiosis hepatis in rats. Toxicol Pathol 30:216–227

    Article  PubMed  Google Scholar 

  • Ma W, Tessarollo L, Hong SB, Bapa M, Southon E, Back TC, Spence S, Lobe CG, Sharma N, Maher GW, Pack S, Vormeyer AO, Guo C, Zbar B, Schmidt LS (2003) Hepatic vascular tumors, angiectasis in multiple organs, and impaired spermatogenesis in mice with conditional inactivation of the VHL gene. Cancer Res 63:5320–5328

    PubMed  CAS  Google Scholar 

  • McIntyre BS, Briski KP, Gapor A, Sylveater PW (2000) Antiproliferative and apoptotic effects of tocopherols and tocotrienols on preneoplastic and neoplastic mouse mammary epithelial cells. Proc Soc Exp Biol Med 224:292–301

    Article  PubMed  CAS  Google Scholar 

  • Miyamoto K, Shiozaki M, Shibata M, Koike M, Uchiyama Y, Gotow T (2009) Very-high-dose alpha-tocopherol supplementation increases blood pressure and causes possible adverse central nervous system effects in stroke-prone spontaneously hypersensitive rats. J Neurosci Res 87:556–566

    Article  PubMed  CAS  Google Scholar 

  • Mo H, Elson CE (1999) Apoptosis and cell-cycle arrest in human and murine tumor cells are initiated by isoprenoids. J Nutr 129:804–813

    PubMed  CAS  Google Scholar 

  • Nakamura Y, Morishita R, Higaki J, Kida I, Aoki M, Moriguchi A, Yamada K, Hayashi S, Yo Y, Nakano H, Matsumoto K, Nakamura T, Ogihara T (1996) Hepatocyte growth factor is a novel member of the endothelium-specific growth factors: additive stimulatory effects of hepatocyte growth factor with basic fibroblast growth factor but not with vascular endothelial growth factor. J Hypertens 14:1067–1072

    Article  PubMed  CAS  Google Scholar 

  • Nakamura H, Furukawa F, Nishikawa A, Miyauchi M, Son HY, Imazawa T, Hirose M (2001) Oral toxicity of a tocotrienol preparation in rats. Food Chem Toxicol 39:799–805

    Article  PubMed  CAS  Google Scholar 

  • Nishikawa T, Tomiya T, Ohtomo N, Inoue Y, Ikeda H, Tejima K, Watanabe N, Tanoue Y, Omata M, Fujiwara K (2007) Stimulation by glutamine and praline of HGF production in hepatic stellate cells. Biochem Biophys Res Commun 363:978–982

    Article  PubMed  CAS  Google Scholar 

  • Pearce BC, Parker RA, Deason ME, Dischino DD, Gillespie E, Qureshi AA, Volk K, Wright JJ (1994) Inhibitors of cholesterol biosynthesis. 2. Hypocholestemic and antioxidant activities of benzopyran and tetrahydronaphthalene analogues of the tocotrienols. J Med Chem 37:526–541

    Article  PubMed  CAS  Google Scholar 

  • Sato K, Kitahara A, Satoh K, Ishikawa T, Tatematsu M, Ito N (1984) The placental form of glutathione S-transferase as a new biomarker protein for preneoplasia in rat chemical hepatocarcinogenesis. Gann 75:199–202

    PubMed  CAS  Google Scholar 

  • Schrmacher P, Geerts A, Pietrangelo A, Dienes HP, Rogler CE (1992) Hepatocyte growth factor/hepatopoietin A is expressed in fat-storing cells from rat liver but not myofibroblast-like cells derived from fat-storing cells. Hepatology 15:5–11

    Article  Google Scholar 

  • Sen CK, Khanna S, Roy S (2004) Tocotrienol: the natural vitamin E to defend the nervous system? Ann NY Acad Sci 1031:127–142

    Article  PubMed  CAS  Google Scholar 

  • Servinova E, Kagan V, Han D, Packer L (1991) Free radical recycling and intramembrane mobility in the antioxidant properties of alpha-tocopherol and alpha-tocotrienol. Free Rad Biol Med 10:263–275

    Article  Google Scholar 

  • Shibata A, Nakagawa K, Sookwong P, Tsuduki T, Tomita S, Shirakawa H, Komai M, Miyazawa T (2008) Tocotrienol inhibits secretion of angionenic factors from human colorectal adenocarcinoma cells by suppressing hypoxia-inducible factor-1 alpha. J Nutr 138:2136–2142

    Article  PubMed  CAS  Google Scholar 

  • Song BL, DeBose-Boyd RA (2006) Insig-dependent ubiquitination and degradation of 3-hydroxy-3-methylglutaryl coenzyme A reductase stimulated by δ- and γ-tocotrienols. J Biol Chem 281:25054–25061

    Article  PubMed  CAS  Google Scholar 

  • Srivastava JK, Gupta S (2006) Tocotrienol-rich fraction of palm oil induces cell cycle arrest and apoptosis selectively in human prostate cancer cells. Biochem Biophys Res Comm 346:447–453

    Article  PubMed  CAS  Google Scholar 

  • Stroebel P, Mayer F, Zerban H, Bannasch P (1995) Spongiotic pericytoma: a benign neoplasma deriving from perisinusoidal (Ito) cells in rat liver. Am J Pathol 146:903–913

    PubMed  CAS  Google Scholar 

  • Suzuki YJ, Tsuchiya M, Wassall SR, Choo YM, Govil G, Kagan VE, Packer L (1993) Structual and dynamic membrane properties of alpha-tocopherol and alpha-tocotrienol: implication to the molecular mechanism of their antioxidant potency. Biochemistry 32:10692–10699

    Article  PubMed  CAS  Google Scholar 

  • Tasaki M, Umemura T, Inoue T, Okamura T, Kuroiwa Y, Ishii Y, Maeda M, Hirose M, Nishikawa A (2008) Induction of characteristic hepatocyte proliferative lesion with dietary exposure of Wistar Hannover rats to tocotrienol for 1 year. Toxicology 250:143–150

    Article  PubMed  CAS  Google Scholar 

  • Uruno A, Sugawara A, Kanatsuka H, Arima S, Taniyama Y, Kudo M, Takeuchi K, Ito S (2004) Hepatocyte growth factor stimulates nitric oxide production through endothelial nitric oxide synthesis activation by the phosphoinositide 3-kinase/Akt pathway and possibly by mitogen-activated protein kinase kinase in vascular endothelial cells. Hypertens Res 27:887–895

    Article  PubMed  CAS  Google Scholar 

  • Uto-Kondo H, Ohmori R, Kiyose C, Kishimoto Y, Saito H, Igarashi O, Kondo K (2009) Tocotrienol suppresses adipocyte differentiation and Akt phosphorylation in 3T3-Li preadipocytes. J Nutr 139:51–57

    PubMed  CAS  Google Scholar 

  • Yap WN, Chang PN, Han HY, Lee DT, Ling MT, Wong YC, Yap YL (2008) Gamma-tocotrienol suppresses prostate cancer cell proliferation and invasion through multiple-signaling pathways. Br J Cancer 99:1832–1841

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Ms. Ayako Kaneko and Yoshimi Komatsu for expert technical assistance in processing histological materials. This work was supported by a Grant-in-Aid for Research on Food Sanitation from the Ministry of Health, Labour and Welfare of Japan.

Author information

Authors and Affiliations

  1. Division of Pathology, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan

    Masako Tasaki, Takashi Umemura, Aki Kijima, Tomoki Inoue, Toshiya Okamura, Yuichi Kuroiwa, Yuji Ishii & Akiyoshi Nishikawa

Authors
  1. Masako Tasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takashi Umemura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aki Kijima
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tomoki Inoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Toshiya Okamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuichi Kuroiwa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuji Ishii
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Akiyoshi Nishikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takashi Umemura.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tasaki, M., Umemura, T., Kijima, A. et al. Simultaneous induction of non-neoplastic and neoplastic lesions with highly proliferative hepatocytes following dietary exposure of rats to tocotrienol for 2 years. Arch Toxicol 83, 1021–1030 (2009). https://doi.org/10.1007/s00204-009-0461-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-009-0461-8

Keywords

Search

Navigation