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Jpn J Cancer Res. 1993 Aug; 84(8): 859–864.
doi: 10.1111/j.1349-7006.1993.tb02058.x
PMCID: PMC5919264
PMID: 8407550

Effects of Chronic Administration of Low Doses of 2‐Ammo‐3,8‐dimethylimidazo‐[4,5‐f]qumoxaline on Glutathione S‐Transferase Placental Form‐positive Foci Development in the Livers of Rats Fed a Choline‐deficient Diet

Hideko Sone,1 Keiji Wakabayashi,corresponding author1 Hiromi Kushida,1 Masako Ochiai,1 Takashi Sugimura,1 and Minako Nagao1
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Abstract

Effects of chronic administration of 2‐amino‐3,8‐dimethylimidazo[4,S‐f]quinoxaline (MeIQx) at the very low doses of 0.4 and 4 ppm, respectively 1000‐ and 100‐fold less than the dose shown to be carcinogenic (400 ppm), on the liver of rats fed a choline‐deficient (CD) diet were examined in terms of glutathione S‐transferase placental form (GST‐P)‐positive foci. Male F344 rats were given CD diet containing 0, 0.4 or 4 ppm MeIQx for 20 or 40 weeks. As controls, rats received choline‐supplemented (CS) diet in the same manner. MeIQx at 4 ppm in the CD diet significantly increased both the number and area of GST‐P‐positive foci, the values being 2.3‐ and 2.1‐fold at 20 weeks and 2.0‐ and 3.3‐fold at 40 weeks, respectively, compared with those observed for CD diet alone. MeIQx at 0.4 ppm in CD diet did not affect the development of GST‐P‐positive foci. No influence of the heterocyclic amine was found in the CS groups, where only very small numbers of minute lesions were observed. The level of MeIQx‐DNA adducts in rats given the CD diet containing 4 ppm MeIQx was 2‐ to 3‐fold lower than that in rats given the CS diet containing 4 ppm MeIQx at 20 and 40 weeks. This result indicates that DNA adduct formation and cell proliferation are both required for the increase of GST‐P‐positive foci in rats fed 4 ppm MeIQx in a CD diet. The above findings strongly suggest that MeIQx could be carcinogenic even at 4 ppm under CD conditions, where liver cell regeneration is continuously occurring.

Keywords: MeIQx, Choline‐deficient diet, GST‐P‐positive foci, Cell proliferation

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Selected References

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1. Sugimura , T.Carcinogenicity of mutagenic heterocyclic amines formed during the cooking process . Mutat. Res. , 150 , 33 – 41 ( 1985. ). [PubMed] [Google Scholar]
2. Sugimura , T.Studies on environmental chemical carcinogenesis in Japan . Science , 233 , 312 – 318 ( 1986. ). [PubMed] [Google Scholar]
3. Sugimura , T.Multistep carcinogenesis: a 1992 perspective . Science , 258 , 603 – 607 ( 1992. ). [PubMed] [Google Scholar]
4. Esumi , H. , Ohgaki , H. , Kohzen , E. , Takayama , S. and Sugimura , T.Induction of lymphoma in CDF1 mice by the food mutagen, 2‐amino‐l‐methyl‐6‐phenylimidazo[4,5‐β]‐pyridine . Jpn. J. Cancer Res. , 80 , 1176 – 1178 ( 1989. ). [PMC free article] [PubMed] [Google Scholar]
5. Ito , N. , Hasegawa , R. , Sano , M. , Tamano , S. , Esumi , H. , Takayama , S. and Sugimura , T.A new colon and mammary carcinogen in cooked food, 2‐amino‐l‐methyI‐6‐phenylimidazo[4,5‐β]pyridine (PhIP) . Carcinogenesis , 12 , 1503 – 1506 ( 1991. ). [PubMed] [Google Scholar]
6. Ohgaki , H. , Hasegawa , H. , Suenaga , M. , Sato , S. , Takayama , S. and Sugimura , T.Carcinogenicity in mice of a mutagenic compound, 2‐amino‐3,8‐dimethylimidazo[4,5‐f]quinoxaline (MeIQx) from cooked foods . Carcinogenesis , 8 , 665 – 668 ( 1987. ). [PubMed] [Google Scholar]
7. Kato , T. , Ohgaki , H. , Hasegawa , H. , Sato , S. , Takayama , S. and Sugimura , T.Carcinogenicity in rats of a mutagenic compound, 2‐amino‐3,8‐dimethylimidazo[4,5‐f]‐quinoxaline . Carcinogenesis , 9 , 71 – 73 ( 1988. ). [PubMed] [Google Scholar]
8. Sugimura , T. , Sato , S. and Wakabayashi , K.Mutagens/carcinogens in pyrolysates of amino acids and proteins and in cooked foods: heterocyclic aromatic amines . In “ Chemical Induction of Cancer ,” ed. Woo Y.‐t. , Lai D. Y. , Arcos J. C. and Argus M. F. , Vol. III , pp. 681 – 710 ( 1988. ). Academic Press; , San Diego [Google Scholar]
9. Zhang , X.‐M. , Wakabayashi , K. , Liu , Z.‐C. , Sugimura , T. and Nagao , M.Mutagenic and carcinogenic heterocyclic amines in Chinese cooked foods . Mutat. Res. , 201 , 181 – 188 ( 1988. ). [PubMed] [Google Scholar]
10. Ushiyama , H. , Wakabayashi , K. , Hirose , M. , Itoh , H. , Sugimura , T. and Nagao , M.Presence of carcinogenic heterocyclic amines in urine of healthy volunteers eating normal diet, but not of inpatients receiving parenteral alimentation . Carcinogenesis , 12 , 1417 – 1422 ( 1991. ). [PubMed] [Google Scholar]
11. Preston‐Martin , S. , Pike , M. C. , Ross , R. K. , Jones , P. A. and Henderson , B. E.Increased cell division as a cause of human cancer . Cancer Res. , 50 , 7415 – 7421 ( 1990. ). [PubMed] [Google Scholar]
12. Tsuda , H. , Takahashi , S. , Yamaguchi , S. , Ozaki , K. and Ito , N.Comparison of initiation potential of 2‐amino‐3‐methylimidazo[4,5‐f]quinoline and 2‐amino‐3,8‐dimethylimidazo[4,5‐f]quinoxaline in an in vivo carcinogen bioassay system . Carcinogenesis , 11 , 549 – 552 ( 1990. ). [PubMed] [Google Scholar]
13. Kleman , M. , Övervik E. , Blanck A. and Gustafsson J.‐Å.The food‐mutagens 2‐amino‐l‐methyl‐6‐phenylixnidazo[4,5‐β]pyridine (PhIP) and 2‐arnino‐3,8‐dimethylimidazo[4,5‐f]quinoxaline (MeIQx) initiate enzyme‐altered hepatic foci in the resistant hepatocyte model . Carcinogenesis , 10 , 1697 – 1700 ( 1989. ). [PubMed] [Google Scholar]
14. Sone , H. , Wakabayashi , K. , Kushida , H. , Sugimura , T. and Nagao , M.Induction of preneoplastic lesions by a low dose of 2‐amino‐3,8‐dimethylimidazo[4,5‐f]quinoxaline (MeIQx) in the livers of rats treated with carbon tetrachloride . Carcinogenesis , 13 , 793 – 797 ( 1992. ). [PubMed] [Google Scholar]
15. Chandar , N. and Lombardi , B.Liver cell proliferation and incidence of hepatocellular carcinomas in rats fed consecutively a choline‐devoid and a choline‐supplemented diet . Carcinogenesis , 9 , 259 – 263 ( 1988. ). [PubMed] [Google Scholar]
16. Shinozuka , H. , Katyal , S. L. and Perera , M. I. R.Choline deficiency and chemical carcinogenesis . Adv. Exp. Med. Biol. , 206 , 253 – 267 ( 1986. ). [PubMed] [Google Scholar]
17. Newberne , P. M.Lipotropic factors and oncogenesis . Adv. Exp. Med. Biol. , 206 , 223 – 251 ( 1986. ). [PubMed] [Google Scholar]
18. Yokota , K. , Singh , U. and Shinozuka , H.Effects of a choline‐deficient diet and a hypolipidemic agent on single glutathione S‐transferase placental form‐positive hepatocytes in rat liver . Jpn. J. Cancer Res. , 81 , 129 – 134 ( 1990. ). [PMC free article] [PubMed] [Google Scholar]
19. Satoh , K. , Kitahara , A. , Soma , Y. , Inaba , Y. , Hatayama , I. and Sato , K.Purification, induction, and distribution of placental glutathione transferase: a new marker enzyme for preneoplastic cells in the rat chemical hepatocarcinogenesis . Proc. Natl. Acad. Sci. USA , 82 , 3964 – 3968 ( 1985. ). [PMC free article] [PubMed] [Google Scholar]
20. 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 effect 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 ( 1988. ). [PubMed] [Google Scholar]
21. Ogiso , T. , Tatematsu , M. , Tamano , S. , Hasegawa , R. and Ito , N.Correlation between medium‐term liver bioassay system data and results of long‐term testing in rats . Carcinogenesis , 11 , 561 – 566 ( 1990. ). [PubMed] [Google Scholar]
22. Aoyama , T. , Gonzalez , F. J. and Gelboin , H. V.Mutagen activation by cDNA‐expressed P1450, P3450, and P450a . Mol. Carcinog. , 1 , 253 – 259 ( 1989. ). [PubMed] [Google Scholar]
23. Sesardic , D. , Rich , K. J. , Edwards , R. J. , Davies , D. S. and Boobis , A. R.Selective destruction of cytochrome P‐450d and associated monooxygenase activity by carbon tetrachloride in the rat . Xenobiotica , 19 , 795 – 811 ( 1989. ). [PubMed] [Google Scholar]
24. Ito , N. , Hasegawa , R. , Shirai , T. , Fukushima , S. , Hakoi , K. , Takaba , K. , Iwasaki , S. , Wakabayashi , K. , Nagao , M. and Sugimura , T.Enhancement of GST‐P positive liver cell foci development by combined treatment of rats with five heterocyclic amines at low doses . Carcinogenesis , 12 , 767 – 772 ( 1991. ). [PubMed] [Google Scholar]
25. Yamashita , K. , Adachi , M. , Kato , S. , Nakagama , H. , Ochiai , M. , Wakabayashi , K. , Sato , S. , Nagao , M. and Sugimura , T.DNA adducts formed by 2‐amino‐3,8‐dimethylimidazo[4,5‐f]quinoxaline in rat liver: doseresponse on chronic administration . Jpn. J. Cancer Res. , 81 , 470 – 476 ( 1990. ). [PMC free article] [PubMed] [Google Scholar]
26. Turteltaub , K. W , Felton , J. S. , Gledhill , B. L , Vogel , J. S. , Southon , J. R. , Caffee , M. W. , Finkel , R. C. , Nelson , D. E. , Proctor , I. D. and Davis , J. C.Accelerator mass spectrometry in biomedical dosimetry: Relationship between low‐level exposure and covalent binding of heterocyclic amine carcinogens to DNA . Proc. Natl. Acad. Sci. USA , 87 , 5288 – 5292 ( 1990. ). [PMC free article] [PubMed] [Google Scholar]
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