Skip to main content
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 2001 Oct;92(10):1018–1025. doi: 10.1111/j.1349-7006.2001.tb01055.x

Differential Effects of Partial Hepatectomy and Carbon Tetrachloride Administration on Induction of Liver Cell Foci in a Model for Detection of Initiation Activity

Hiroki Sakai 1,2, Tetsuya Tsukamoto 1, Masami Yamamoto 1, Norimitsu Shirai 1,2, Takeshi lidaka 1,2, Tokuma Yanai 2, Toshiaki Masegi 2, Masae Tatematsu 1,
PMCID: PMC5926621  PMID: 11676851

Abstract

Differential effects of partial hepatectomy (PH) and carbon tetrachloride (CC14) administration on induction of glutathione S‐transferase placental form (GST‐P)‐positive foci were investigated in a model for detection of initiation activity. Firstly, we surveyed cell proliferation kinetics and fluctuation in cytochrome P450 (CYP) mRNA levels by means of relative‐quantitative real‐time reverse transcriptase‐polymerase chain reaction (RT‐PCR) and CYP 2E1 apoprotein amount by immuno‐blotting (experiment I) after PH or CC14 administration. Next, to assess the interrelationships among cell proliferation, fluctuation of CYPs after PH or CC14 administration and induction of liver cell foci, the non‐hepatocarcinogen, 1,2‐dimethylhydrazine (DMH) was administered to 7‐week‐old male F344 rats and initiated populations were selected using the resistant hepatocyte model (experiment II). In experiment I, the values of all CYP isozyme mRNAs after PH or CC14 administration were drastically decreased at the 12‐h tune point. From 72 h, mRNAs for all CYP isozymes began increasing, with complete recovery after 7 days. The CYP 2E1 apoprotein content in the PH group fluctuated weakly, whereas in the CC14 group it had decreased rapidly after 12 h and was still low at the 48 h point. In experiment II, induction of GST‐P‐positive foci was related to cell kinetics in the PH group, with about a 6‐h time lag between tune for carcinogen administration giving greatest induction of GST‐P‐positive foci and peaks in bromodeoxyuridine (BrdU) labeling, presumably due to the necessity for bioactivation of DMH. With CC14 administration, induction of foci appeared dependent on the recovery of CYP 2E1. In conclusion, PH was able to induce cell proliferation with maintenance of CYP 2E1, therefore being advantageous for induction of liver cell foci in models to detect initiation activity.

Keywords: Medium‐term bioassay, Partial hepatectomy, Carbon tetrachloride, GST‐P‐positive foci, Initiation

Full Text

The Full Text of this article is available as a PDF (187.9 KB).

REFERENCES

  • 1. ) Ito , N. , Hasegawa , R. , Imaida , K. , Hirose , M. and Shirai , T.Medium‐term liver and multi‐organ carcinogenesis bioas‐says for carcinogens and chemopreventive agents . Exp. Toxicol. Pathol , 48 , 113 – 119 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 2. ) Ito , N. , Tsuda , H. , Tatematsu , M. , Inoue , T. , Tagawa , Y. , Aoki , T. , Uwagawa , S. , Kagawa , M. , Ogiso , T. , Masui , T. , Imaida , K. , Fukushima , S. and Asamoto , M.Enhancing effects of various hepatocarcinogens on induction of pre‐neoplastic glutathione S‐transferase placental form positive foci in rats–an approach for a new medium‐term bioassay system . Carcinogenesis , 9 , 387 – 394 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 3. ) Tsuda , H. , Lee , G. and Farber , E.Induction of resistant hepatocytes as a new principle for a possible short‐term in vivo test for carcinogens . Cancer Res. , 40 , 1157 – 1164 ( 1980. ). [PubMed] [Google Scholar]
  • 4. ) Tezuka , N. , Tada , M. , Kojima , M. , Nakanishi , H. , Mori , A. and Tatematsu , M.Effects of partial hepatectomy on initiation of liver cell foci by 4‐nitroquinoline 1‐oxide, a non‐hepatocarcinogen, and generation of DNA adducts in rats . Cancer Lett. , 89 , 89 – 94 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 5. ) Kobayashi , K. , Mutai , M. , Goto , K. , Inada , K. , Tsukamoto , T. , Nakanishi , H. and Tatematsu , M.Effects of carbon tet‐rachloride administration on initiation of liver cell foci by the non‐hepatocarcinogens N‐methyl‐N'‐nitro‐N‐nitro‐soguanidine (MNNG) and benzo(a)pyrene (B(a)P) . Cancer Lett , 118 , 55 – 60 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 6. ) Tatematsu , M. , Mera , Y. , Inoue , T. , Sato , K. , Sato , K. and Ito , N.Stable phenotypic expression of glutathione S‐transferase placental type and unstable phenotypic expression of gamma‐glutamyltransferase in rat liver preneoplastic and neoplastic lesions . Carcinogenesis , 9 , 215 – 220 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 7. ) Sakai , H. , Tsukamoto , T. , Yamamoto , M. , Yanai , T. , Masegi , T. , Inada , K. , Nakanishi , H. and Tatematsu , M.Summation of initiation activities of low doses of the non‐ hepatocarcinogen 1,2‐dimethylhydrazine in the liver after carbon tetrachloride administration . Cancer Lett. , 148 , 59 – 63 ( 2000. ). [DOI] [PubMed] [Google Scholar]
  • 8. ) Aitio , A. , Aitio , M.‐L. , Camus , A.‐M. , Cardis , E. and Bartsch , H.Cytochrome P‐450 isozyme pattern is related to individual susceptibility to diethylnitrosamine‐induced liver cancer in rats . Jpn. J. Cancer Res. , 82 , 146 – 156 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. ) Kawajiri , K. and Fujii‐Kuriyama , Y.P450 and human cancer . Jpn. J. Cancer Res. , 82 , 1325 – 1335 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. ) Tsukamoto , T. , Fukami , H. , Yamanaka , S. , Yamaguchi , A. , Nakanishi , H. , Sakai , H. , Aoki , I. and Tatematsu , M.Hex‐osaminidase‐altered aberrant crypts, carrying decreased hexosaminidase α and β subunit mRNAs, in colon of 1,2‐dimethylhydrazine‐treated rats . Jpn. J. Cancer Res. , 92 , 109 – 118 ( 2001. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. ) Tatematsu , M. , Tsuda , H. , Shirai , T. , Masui , T. and Ito , N.Placental glutathione S‐transferase (GST‐P) as a new marker for hepatocarcinogenesis: in vivo short‐term screening for hepatocarcinogens . Toxicol. Pathol. , 15 , 60 – 68 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 12. ) Morris , D. L. and Davila , J. C.Analysis of rat cytochrome P450 isoenzyme expression using semi‐quantitative reverse transcriptase‐polymerase chain reaction (RT‐PCR) . Bio-chem. Pharmacol. , 52 , 781 – 792 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 13. ) Nudel , U. , Zakut , R. , Shani , M. , Neuman , S. , Levy , Z. and Yaffe , D.The nucleotide sequence of the rat cytoplasmic beta‐actin gene . Nucleic Acids Res. , 11 , 1759 – 1771 ( 1983. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. ) Buhler , R. , Lindros , K. O. , Nordling , A. , Johansson , I. and Ingelman‐Sundberg , M.Zonation of cytochrome P450 isozyme expression and induction in rat liver . Eur. J. Bio-chem. , 204 , 407 – 412 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) Edwards , R. J. , Singleton , A. M. , Murray , B. P. , Davies , D. S. and Boobis , A. R.Short synthetic peptides exploited for reliable and specific targeting of antibodies to the C‐termini of cytochrome P450 enzymes . Biochem. Pharmacol. , 49 , 39 – 47 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 16. ) Burke , M. D. and Mayer , R. T.Ethoxyresorufin: direct flu‐orimetric assay of a microsomal O‐dealkylation which is preferentially inducible by 3‐methylcholanthrene . Drug Metab. Dispos. , 2 , 583 – 588 ( 1974. ). [PubMed] [Google Scholar]
  • 17. ) Trautwein , C. , Rakemann , T. , Obermayer‐Straub , P. , Niehof , M. and Manns , M. P.Differences in the regulation of cytochrome P450 family members during liver regeneration . J. HepatoL , 26 , 48 – 54 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 18. ) Lowry , O. H. , Rosebrough , N. J. , Fair , A. L. and Randall , F. J.Protein measurement with the Folin phenol reagent . J. Biol. Chem. , 193 , 265 – 275 ( 1951. ). [PubMed] [Google Scholar]
  • 19. ) Laemmli , U. K.Cleavage of structural proteins during the assembly of the head of bacteriophage T4 . Nature , 227 , 680 – 685 ( 1970. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Padgham , C. R. , Boyle , C. C. , Wang , X. J. , Raleigh , S. M. , Wright , M. C. and Paine , A. J.Alteration of transcription factor mRNAs during the isolation and culture of rat hepatocytes suggests the activation of a proliferative mode underlies their de‐differentiation . Biochem. Biophys. Res. Commun. , 197 , 599 – 605 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Ishizuka , M. , Yoshino , S. , Yamamoto , Y. , Yamamoto , H. , Imaoka , S. , Funae , Y. , Masuda , M. , Iwata , H. , Kazusaka , A. and Fujita , S.Isozyme selective alterations of the expression of cytochrome P450 during regeneration of male rat liver following partial hepatectomy . Xenobiotica , 27 , 923 – 931 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 22. ) Wang , P. Y. , Kaneko , T. , Tsukada , H. , Nakano , M. , Nakajima , T. and Sato , A.Time courses of hepatic injuries induced by chloroform and by carbon tetrachloride: comparison of biochemical and histopathological changes . Arch. Toxicol. , 71 , 638 – 645 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 23. ) Slater , T. F.Free‐radical mechanisms in tissue injury . Bio-chem. J. , 222 , 1 – 15 ( 1984. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. ) Kalyanaraman , B. , Mason , R. P. , Perez‐Reyes , E. , Chignell , C. F. , Wolf , C. R. and Philpot , R. M.Characterization of the free radical formed in aerobic microsomal incubations containing carbon tetrachloride and NADPH . Biochem. Biophys. Res. Commun. , 89 , 1065 – 1072 ( 1979. ). [DOI] [PubMed] [Google Scholar]
  • 25. ) Osawa , Y. , Martin , B. M. , Griffin , P. R. , Yates , J. R. D. , Shabanowitz , J. , Hunt , D. F. , Murphy , A. C. , Chen , L. , Cotter , R. J. and Pohl , L. R.Metabolism‐based covalent bonding of the heme prosthetic group to its apoprotein during the reductive debromination of BrCCl3 by myoglobin . J. Biol. Chem. , 265 , 10340 – 10346 ( 1990. ). [PubMed] [Google Scholar]
  • 26. ) Roberts , B. J.Evidence of proteasome‐mediated cyto‐chrome P‐450 degradation . J. Biol. Chem. , 272 , 9771 – 9778 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 27. ) Druckrey , H.Production of colonic carcinomas by 1,2‐dialkylhydrazines and azoalkanes . In “ Carcinoma of the Colon and Antecedent Epithelium ” ed. Burdette W. J. , pp. 267 – 279 ( 1970. ). W. J. Charles C. Thomas; , Springfield , IL . [Google Scholar]
  • 28. ) Fiala , E. S.Investigations into the metabolism and mode of action of the colon carcinogens 1,2‐dimethylhydrazine and azoxymethane . Cancer , 40 , 2436 – 2445 ( 1977. ). [DOI] [PubMed] [Google Scholar]
  • 29. ) Sohn , O. S. , Ishizaki , H. , Yang , C. S. and Fiala , E. S.Metabolism of azoxymethane, methylazoxymethanol and N‐nitrosodimethylamine by cytochrome P450IIE1 . Car-cinogenesis , 12 , 127 – 131 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 30. ) Lee , V. M. , Cameron , R. G. and Archer , M. C.Zonal location of compensatory hepatocyte proliferation following chemically induced hepatotoxicity in rats and humans . Toxicol. Pathol. , 26 , 621 – 627 ( 1998. ). [DOI] [PubMed] [Google Scholar]

Articles from Japanese Journal of Cancer Research : Gann are provided here courtesy of Wiley

RESOURCES