研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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Genetic Predisposition to Pre-B Lymphomas in SL/Kh Strain Mice 査読有り国際誌

Yamada Y., Matsushiro H., Ogawa M.S., Okamoto K., Nakakuki Y., Toyokuni S., Fukumoto M., Hiai H.

Cancer Research 54 巻 ( 2 ) 頁： 403 - 407 1994年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancer Research

Genetic predisposition of SL/Kh mice to spontaneous pre-B lymphomas was investigated in crosses between SL/Kh and NFS/N, another inbred strain of mice lacking endogenous ecotropic provirus and spontaneous lymphoma. (SL/Kh x NFS/N) F! hybrids developed lymphomas similar to those in SL/Kh but at a lower frequency and with a longer latent period. Of 83 backcross mice to NFS/N, 22 developed hemopoietic tumors: 8 were diffuse lymphoblastic lymphomas; 2 were myeloid leukemias arising by 12 months of age; and 12 were follicular center cell lymphomas found later in life. Of 6 endogenous ecotropic proviruses in SL/Kh, 2 were expressed in (SL/Kh x NFS) Fx backcrossed to NFS. One, encoded by a 27-kilobase EcoSl fragment, was closely linked to Gpi-1” on chromosome 7 and its expression seemed to be a prerequisite for the occurrence of all types of hemopoietic tumors. Microsatellite analysis of the backcross generation revealed multiple host genetic factors determining susceptibility to tumors. An allele derived from SL/Kh, mapped in the major histocompatibility locus on chromosome 17, was essential for development of early onset tumors. This locus was designated as Esl-1 (early lymphoma of SL-1). On the other hand, follicular center cell lymphomas developed mostly in the backcross mice homozygous for the NFS/N derived allele at the D4MIT17-linked locus, designated as foc-1 (follicular center cell lymphoma-1), on chromosome 4. © 1994, American Association for Cancer Research. All rights reserved.

DOI： 10.1242/dev.02004

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Genetic Predisposition to Pre-B Lymphomas in SL/Kh Strain Mice 国際誌

Yamada Y, Matsushiro H, Ogawa M.S, Okamoto K, Nakakuki Y, Toyokuni S, Fukumoto M, Hiai H

Cancer Research 54 巻 ( 2 ) 頁： 403 - 407 1994年1月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancer Research

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Abnormal Bone Marrow B-Cell Differentiation in Pre-B Lymphoma-prone SL/Kh Mice 査読有り国際誌

Okamoto K., Yamada Y., Ogawa M.S., Toyokuni S., Nakakuki Y., Ikeda H.

Cancer Research 54 巻 ( 2 ) 頁： 399 - 402 1994年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancer Research

SL/Kh mice spontaneously develop pre-B lymphomas with surface phenotypes of B220+, BP-1+, Thy-1-, and surface immunoglobulin negative. The immunoglobulin heavy chain of lymphoma is clonally rearranged but the light chain gene remains in germline configuration. Studying prelymphoma stage SL/Kh bone marrow (BM), we found unusual multiclonal expansion of BP-1+ pre-B cells [34.8 + 5.8% (mean - SD)] by 4 weeks of age, whereas there were far fewer of such cells in most other laboratory strains (8 - 5%). The BP-1+ cells did not express surface immunoglobulin, Thy-1.1, or c-kit. Therefore, they seemed to belong to the pre-B II category. Increased numbers of BP-1+ cells were seen in Fx hybrids between SL/Kh and NFS/N; thus it was apparently a dominant heritable property of SL/Kh mice. Emergence of this population was independent of expression of endogenous ecotropic virus, since they were present in BMs of the Yt hybrid to C4W (Fv-4r) and were not inhibited by neonatal injection of maternal resistance factor. In the radiation chimeras SL/Kh - BALB/c, BP-1+ cells appeared abundantly (29.0 - 3.8%), whereas in the reciprocal chimeras BALB/c - SL/Kh, for fewer (5.5 - 2.3%) appeared. Therefore, expansion of BP-1+ cells in prelymphomatous BM is a property of SL/Kh stem cells rather than BM microenvironments. © 1994, American Association for Cancer Research. All rights reserved.

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ALTERATION OF THE DEOXYGUANINE NUCLEOTIDES TO 8-HYDROXYDEOXYGUANOSINE IN HUMAN RENAL-CELL CARCINOMA

OKAMOTO, K; YOSHIDA, O; HATTORINAKAKUKI, Y; HIAI, H; TOYOKUNI, S

FRONTIERS OF REACTIVE OXYGEN SPECIES IN BIOLOGY AND MEDICINE 1058 巻頁： 447 - 448 1994年

FORMATION OF 4-HYDROXY-2-NONENAL-MODIFIED PROTEINS IN THE RENAL PROXIMAL TUBULES OF RATS TREATED WITH A RENAL CARCINOGEN, FERRIC NITRILOTRIACETATE

TOYOKUNI, S; UCHIDA, K; OKAMOTO, K; HATTORINAKAKUKI, Y; HIAI, H; STADTMAN, ER

FRONTIERS OF REACTIVE OXYGEN SPECIES IN BIOLOGY AND MEDICINE 1058 巻頁： 171 - 172 1994年

FORMATION OF 4-HYDROXY-2-NONENAL-MODIFIED PROTEINS IN THE RENAL PROXIMAL TUBULES OF RATS TREATED WITH A RENAL CARCINOGEN, FERRIC NITRILOTRIACETATE 国際誌

TOYOKUNI, S, UCHIDA, K, OKAMOTO, K, HATTORINAKAKUKI, Y, HIAI, H, STADTMAN, ER

FRONTIERS OF REACTIVE OXYGEN SPECIES IN BIOLOGY AND MEDICINE 1058 巻頁： 171 - 172 1994年

ALTERATION OF THE DEOXYGUANINE NUCLEOTIDES TO 8-HYDROXYDEOXYGUANOSINE IN HUMAN RENAL-CELL CARCINOMA 査読有り国際誌

OKAMOTO, K, YOSHIDA, O, HATTORINAKAKUKI, Y, HIAI, H, TOYOKUNI, S

FRONTIERS OF REACTIVE OXYGEN SPECIES IN BIOLOGY AND MEDICINE 1058 巻頁： 447 - 448 1994年

ABNORMAL BONE-MARROW B-CELL DIFFERENTIATION IN PRE-B LYMPHOMA-PRONE SL/KH MICE

OKAMOTO, K; YAMADA, Y; SHIMADA, M; TOYOKUNI, S; NAKAKUKI, Y; HIAI, H

EXPERIMENTAL HEMATOLOGY 21 巻 ( 8 ) 頁： 1126 - 1126 1993年8月

GENETIC PREDISPOSITION TO PRE-B LYMPHOMAS IN SL/KH STRAIN MICE

YAMADA, Y; SHIMADA, M; OKAMOTO, K; TOYOKUNI, S; NAKAKUKI, Y; FUKUMOTO, M; HIAI, H

EXPERIMENTAL HEMATOLOGY 21 巻 ( 8 ) 頁： 1118 - 1118 1993年8月

INDUCTION OF OXIDATIVE SINGLE-STRAND AND DOUBLE-STRAND BREAKS IN DNA BY FERRIC CITRATE

TOYOKUNI S, SAGRIPANTI JL

FREE RADICAL BIOLOGY AND MEDICINE 15 巻 ( 2 ) 頁： 117 - 123 1993年8月

INDUCTION OF OXIDATIVE SINGLE-STRAND AND DOUBLE-STRAND BREAKS IN DNA BY FERRIC CITRATE 査読有り

S TOYOKUNI, JL SAGRIPANTI

FREE RADICAL BIOLOGY AND MEDICINE 15 巻 ( 2 ) 頁： 117 - 123 1993年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

The relative risk of primary hepatocellular carcinoma in genetic hemochromatosis (GH) is estimated at over 200 times as that of control populations. Recently, ferric ion chelated to citrate (Fe-citrate) was identified as the major non-transferrin-bound iron in the serum of GH patients. We investigated whether low concentration of Fe-citrate plus reductant could damage supercoiled plasmid DNA under physiological pH and ionic strength. Incubation of Fe-citrate with either H2O2, L-ascorbate, or L-cysteine induced single- and double-strand breaks in supercoiled plasmid pZ189 in a concentration- and time-dependent fashion. DNA strand breaks produced by Fe-citrate plus H2O2 increased at reduced pH (less-than-or-equal-to 6.9). Catalase and free radical scavengers inhibited the DNA breakage produced by Fe-citrate in combination with each reductant, suggesting that H2O2 and finally .OH are responsible DNA damaging species. The catalytic ability of Fe-citrate to induce DNA strand breaks, particularly double-strand breaks (DSBs), may contribute to the carcinogenic processes observed in GH.

DOI： 10.1016/0891-5849(93)90050-5

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Induction of oxidative single- and double-strand breaks in DNA by ferric citrate

Toyokuni S., Sagripanti J.

Free Radical Biology and Medicine 15 巻 ( 2 ) 頁： 117 - 123 1993年8月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Free Radical Biology and Medicine

The relative risk of primary hepatocellular carcinoma in genetic hemochromatosis (GH) is estimated at over 200 times as that of control populations. Recently, ferric ion chelated to citrate (Fe-citrate) was identified as the major non-transferrin-bound iron in the serum of GH patients. We investigated whether low concentration of Fe-citrate plus reductant could damage supercoiled plasmid DNA under physiological pH and ionic strength. Incubation of Fe-citrate with either H2O2, l-ascorbate, or l-cysteine induced single- and double-strand breaksin supercoiled plasmid pZ189 in a concentration- and time-dependent fashion. DNA strand breaks produced by Fe-citrate plus H2O2 increased at reduced pH (≤ 6.9). Catalase and free radical scavengers inhibited the DNA breakage produced by Fe-citrate in combination with each reductant, suggesting that H2O2 and finally .OH are responsible DNA damaging species. The catalytic ability of Fe-citrate to induce DNA strand breaks, particularly double-strand breaks (DSBs), may contribute to the carcinogenic processes observed in GH. © 1993.

DOI： 10.1016/0891-5849(93)90050-5

Scopus

GENETIC PREDISPOSITION TO PRE-B LYMPHOMAS IN SL/KH STRAIN MICE 国際誌

YAMADA, Y, SHIMADA, M, OKAMOTO, K, TOYOKUNI, S, NAKAKUKI, Y, FUKUMOTO, M, HIAI, H

EXPERIMENTAL HEMATOLOGY 21 巻 ( 8 ) 頁： 1118 - 1118 1993年8月

ABNORMAL BONE-MARROW B-CELL DIFFERENTIATION IN PRE-B LYMPHOMA-PRONE SL/KH MICE 査読有り国際誌

OKAMOTO, K, YAMADA, Y, SHIMADA, M, TOYOKUNI, S, NAKAKUKI, Y, HIAI, H

EXPERIMENTAL HEMATOLOGY 21 巻 ( 8 ) 頁： 1126 - 1126 1993年8月

GLUTATHIONE CYCLE DEPENDENCY OF FERRIC NITRILOTRIACETATE-INDUCED LIPID-PEROXIDATION IN MOUSE PROXIMAL RENAL TUBULES

OKADA S, MINAMIYAMA Y, HAMAZAKI S, TOYOKUNI S, SOTOMATSU A

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS 301 巻 ( 1 ) 頁： 138 - 142 1993年2月

GLUTATHIONE CYCLE DEPENDENCY OF FERRIC NITRILOTRIACETATE-INDUCED LIPID-PEROXIDATION IN MOUSE PROXIMAL RENAL TUBULES

OKADA S, MINAMIYAMA Y, HAMAZAKI S, TOYOKUNI S, SOTOMATSU A

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS 301 巻 ( 1 ) 頁： 138 - 142 1993年2月

Glutathione cycle dependency of ferric nitrilotriacetate-induced lipid peroxidation in mouse proximal renal tubules

Okada S., Minamiyama Y., Hamazaki S., Toyokuni S., Sotomatsu A.

Archives of Biochemistry and Biophysics 301 巻 ( 1 ) 頁： 138 - 142 1993年2月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Archives of Biochemistry and Biophysics

Parenteral administration of ferric nitrilotriacetate (Fe-NTA), a known carcinogen in mouse and rat kidneys, enhances iron-dependent lipid peroxidation (LP) and causes acute renal tubular necrosis. We assume that filtered Fe-NTA in vivo is rapidly reduced by cysteine, a component of glutathione which is hydrolyzed by γ-GTP and dipeptidase, and that this reduced iron initiates lipid peroxidation in the lumen. In addition, the fatty acid composition of phospholipids between the cortex and the medulla may differ, because only the proximal tubules (which are located mainly in the cortex) are known to be vulnerable to LP. We tested these assumptions in the present study. Gas chromatographic determination of fatty acid composition in five male and five female 6-week-old normal ddY mice showed the ratio of polyunsaturated fatty acids to saturated fatty acids plus C18:1, a single double-bond fatty acid, to be 0.98 ± 0.08 (av ± SD) in the male cortex and 1.00 ± 0.08 in the female cortex. In the male and female medulla, however, it was 0.78 ± 0.09 (P < 0.05, vs cortex) and 0.68 ± 0.04 (P < 0.01, vs cortex), respectively. Pretreatment of the animals with buthionine sulfoximine, a glutathione synthetase inhibitor, and a procedure that reduces total glutathione content in the kidneys, suppressed LP. Reduced thiobarbituric acid reactive substances were also observed in animals treated with AT-125, a γ-GTP inhibitor, and in animals with immature γ-GTP activity. These results are consistent with our assumptions. © 1993 Academic Press, Inc.

DOI： 10.1006/abbi.1993.1125

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DNA SINGLE-STRAND AND DOUBLE-STRAND BREAKS PRODUCED BY FERRIC NITRILOTRIACETATE IN RELATION TO RENAL TUBULAR CARCINOGENESIS

TOYOKUNI S, SAGRIPANTI JL

CARCINOGENESIS 14 巻 ( 2 ) 頁： 223 - 227 1993年2月

DNA SINGLE-STRAND AND DOUBLE-STRAND BREAKS PRODUCED BY FERRIC NITRILOTRIACETATE IN RELATION TO RENAL TUBULAR CARCINOGENESIS

TOYOKUNI S, SAGRIPANTI JL

CARCINOGENESIS 14 巻 ( 2 ) 頁： 223 - 227 1993年2月

DNA single- and double-strand breaks produced by ferric nitrilotriacetate in relation to renal tubular carcinogenesis

Toyokuni S., Sagripanti J.

Carcinogenesis 14 巻 ( 2 ) 頁： 223 - 227 1993年2月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Carcinogenesis

Fe(III) bound to a chelator, nitrilotriacetate (NTA), has been reported to induce a high frequency of adenocarcinoma localized to the proximal tubules of the kidney in rodents. In order to examine possible mechanisms for the carcinogenic activity, we investigated the in vitro production of single- and double-strand breaks in DNA mediated by iron alone or Fe-NTA chelate using supercoiled plasmid pZ189. Neither Fe(III) nor NTA alone broke DNA. Fe(III) plus NTA together mediated the efficient oxidative production of DNA single-and double-strand breaks in the presence of reducing agents (ascorbate » H2O2 > cysteine). The Fe(III): NTA ratio (1:4) that was found to be optimal for DNA strand breakage was similar to the ratio that produced adenocarcinomas in rodents. Maximal Fe-NTA-mediated DNA damage in vitro was induced under conditions of neutral pH, low ionic strength, presence of reducing agent and absence of albumin. These conditions are present exclusively in the cortical proximal tubules of the kidney, the only location where toxicity and carcinogenicity of Fe-NTA has been observed. Thus, localized DNA damage may explain the anatomic site preferred by Fe-NTA-induced carcinogenesis. © 1993 Oxford University Press.

DOI： 10.1093/carcin/14.2.223

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