33 results on '"Kimiko Amanuma"'
Search Results
2. Data from Enhanced Spontaneous and Benzo(a)pyrene-Induced Mutations in the Lung of Nrf2-Deficient gpt Delta Mice
- Author
-
Masayuki Yamamoto, Takehiko Nohmi, Ken Itoh, Ken-ichi Masumura, Hirohisa Takano, Kyoko Hiyoshi, Michi Matsumoto, Kimiko Amanuma, Akiko H. Hashimoto, and Yasunobu Aoki
- Abstract
The lung is an organ that is sensitive to mutations induced by chemicals in ambient air, and transgenic mice harboring guanine phosphoribosyltransferase (gpt) gene as a target gene are a well-established model system for assessing genotoxicity in vivo. Transcription factor Nrf2 mediates inducible and constitutive expression of cytoprotective enzymes against xenobiotics and mutagens. To address whether Nrf2 is also involved in DNA protection, we generated nrf2+/−::gpt and nrf2−/−::gpt mice. The spontaneous mutation frequency of the gpt gene in the lung was approximately three times higher in nrf2-null (nrf2−/−) mice than nrf2 heterozygous (nrf2+/−) and wild-type (nrf2+/+) mice, whereas in the liver, the mutation frequency was higher in nrf2−/− and nrf2+/− mice than in nrf2+/+ wild-type mice. By contrast, no difference in mutation frequency was observed in testis among the three genotypes. A single intratracheal instillation of benzo(a)pyrene (BaP) increased the lung mutation frequency 3.1- and 6.1-fold in nrf2+/− and nrf2−/− mice, respectively, compared with BaP-untreated nrf2+/− mice, showing that nrf2−/− mice are more susceptible to genotoxic carcinogens. Surprisingly, mutation profiles of the gpt gene in BaP-treated nrf2+/− mice was substantially different from that in BaP-untreated nrf2−/− mice. In nrf2−/− mice, spontaneous and BaP-induced mutation hotspots were observed at nucleotides 64 and 140 of gpt, respectively. These results thus show that Nrf2 aids in the prevention of mutations in vivo and suggest that Nrf2 protects genomic DNA against certain types of mutations. [Cancer Res 2007;67(12):5643–8]
- Published
- 2023
3. Supplementary Table 4 from Enhanced Spontaneous and Benzo(a)pyrene-Induced Mutations in the Lung of Nrf2-Deficient gpt Delta Mice
- Author
-
Masayuki Yamamoto, Takehiko Nohmi, Ken Itoh, Ken-ichi Masumura, Hirohisa Takano, Kyoko Hiyoshi, Michi Matsumoto, Kimiko Amanuma, Akiko H. Hashimoto, and Yasunobu Aoki
- Abstract
Supplementary Table 4 from Enhanced Spontaneous and Benzo(a)pyrene-Induced Mutations in the Lung of Nrf2-Deficient gpt Delta Mice
- Published
- 2023
4. Supplementary Table 2 from Enhanced Spontaneous and Benzo(a)pyrene-Induced Mutations in the Lung of Nrf2-Deficient gpt Delta Mice
- Author
-
Masayuki Yamamoto, Takehiko Nohmi, Ken Itoh, Ken-ichi Masumura, Hirohisa Takano, Kyoko Hiyoshi, Michi Matsumoto, Kimiko Amanuma, Akiko H. Hashimoto, and Yasunobu Aoki
- Abstract
Supplementary Table 2 from Enhanced Spontaneous and Benzo(a)pyrene-Induced Mutations in the Lung of Nrf2-Deficient gpt Delta Mice
- Published
- 2023
5. Supplementary Table 3 from Enhanced Spontaneous and Benzo(a)pyrene-Induced Mutations in the Lung of Nrf2-Deficient gpt Delta Mice
- Author
-
Masayuki Yamamoto, Takehiko Nohmi, Ken Itoh, Ken-ichi Masumura, Hirohisa Takano, Kyoko Hiyoshi, Michi Matsumoto, Kimiko Amanuma, Akiko H. Hashimoto, and Yasunobu Aoki
- Abstract
Supplementary Table 3 from Enhanced Spontaneous and Benzo(a)pyrene-Induced Mutations in the Lung of Nrf2-Deficient gpt Delta Mice
- Published
- 2023
6. In Vivo Mutagenesis Caused by Diesel Exhaust in the Testis of gpt delta Transgenic Mice
- Author
-
Akiko H. Hashimoto, Takehiko Nohmi, Yasunobu Aoki, Kenichi Masumura, and Kimiko Amanuma
- Subjects
Delta ,Genetically modified mouse ,Diesel exhaust ,Social Psychology ,In vivo ,business.industry ,Chemistry ,Genetics ,Mutagenesis (molecular biology technique) ,Environmental Science (miscellaneous) ,business ,Molecular biology ,Biotechnology - Published
- 2009
7. Molecular Pathology in Atherosclerosis: The Mechanism How Cholesteryl Ester Accumulates in Atheromatous Aorta
- Author
-
Kimiko Amanuma, Yasuko Yagyu, Hiroyuki Itabe, Keiji Nakagami, Yasuyuki Fujimoto, Tatsuya Takano, Chieko Mineo, Eiko Fujita, Junji Kimura, Yusuke Higashi, Ryoichi Hashita, Masahiro Mori, Ryuichiro Sato, and Tsuneo Imanaka
- Subjects
medicine.drug_class ,Pharmaceutical Science ,Apoptosis ,Monoclonal antibody ,Epitope ,chemistry.chemical_compound ,medicine ,Animals ,Humans ,Macrophage ,cardiovascular diseases ,Aorta ,Foam cell ,Pharmacology ,Cholesterol ,Antibodies, Monoclonal ,Atherosclerosis ,medicine.disease ,Cell biology ,Lipoproteins, LDL ,Atheroma ,chemistry ,Cholesteryl ester ,lipids (amino acids, peptides, and proteins) ,Cholesterol Esters ,Foam Cells ,Lipoprotein - Abstract
To study how cholesterol accumulates in atheroma, novel monoclonal antibodies were developed, using crude homogenate of atheroma as immunogens. 212D monoclonal antibody recognizing extra cellular matrix with lipid-laden deposits was selected by histochemical staining. The antigen was deduced vitronectin from cDNA library. DLH3 monoclonal antibody recognizing oxidized LDL, epitope of which was 5- or 9-phosphatidylcholine. Significant correlations between oxidized LDL and coronary heart disease (CHD) patients were observed from clinical study. 256C monoclonal antibody recognizing atheromatous lesions in human aorta was selected. Epitope must be PC-cholesterol complex which may involve in foam cell rupture. Atherogenesis will be discussed from the aspects of these antibodies. Our working hypothesis is required to elucidate the mechanism. Denatured lipoproteins (either oxidized lipoprotein or ruptured foam cells) may induce atheroma. Oxidation of lipoprotein may be taken place both in foam cells and/or extra cellular matrix, and macrophage eliminate these denatured lipoproteins and become foam cells. The foam cells are ruptured by either apoptosis or necrosis afterward, and hydrophobic fragments of foam cells dispersed in extra cellular space, which destroys the function of biological membrane. Since biological function could be maintained by segregation of hydrophilic circumstances, macrophages uptake these fragmented material and oxidized lipoprotein to maintain the function. This vicious spiral may enhance chronically the atheroma.
- Published
- 2008
8. Mutagenicity of 2-[2-(acetylamino)-4-[bis(2-hydroxyethyl)amino]-5-methoxyphenyl]-5-amino-7-bromo-4-chloro-2H-benzotriazole (PBTA-6) and benzo[a]pyrene (BaP) in the gill and hepatopancreas of rpsL transgenic zebrafish
- Author
-
Tetsushi Watanabe, Masato Nagaya, Yukari Totsuka, Yasunobu Aoki, Kimiko Amanuma, Suguru Tone, Keiji Wakabayashi, and Michi Matsumoto
- Subjects
Gills ,Gill ,animal structures ,Health, Toxicology and Mutagenesis ,Mutant ,Hepatopancreas ,Ames test ,Animals, Genetically Modified ,chemistry.chemical_compound ,Salmonella ,In vivo ,Benzo(a)pyrene ,Genetics ,Animals ,Point Mutation ,Zebrafish ,biology ,Mutagenicity Tests ,fungi ,Triazoles ,biology.organism_classification ,Molecular biology ,chemistry ,Toxicity ,Pyrene ,Water Pollutants, Chemical ,Mutagens - Abstract
We examined the in vivo mutagenicity of 2-[2-(acetylamino)-4-[bis(2-hydroxyethyl)amino]-5-methoxyphenyl]-5-amino-7-bromo-4-chloro-2H-benzotriazole (PBTA-6) and benzo[a]pyrene (BaP) by using transgenic (Tg) zebrafish carrying the mutational target gene rpsL. PBTA-6 is one of the PBTA-type compounds that were recently identified in highly mutagenic river water in Japan. BaP is a well-known contaminant that is frequently found in polluted water. Both compounds are potent mutagens, as determined by using the Ames test employing S9 mix and Salmonella. Adult rpsL Tg zebrafish were exposed to 0, 7, or 10 mg/L PBTA-6 or 0, 1.5, or 3 mg/L BaP for 96 h in a water bath and the mutations in their gills and hepatopancreata were measured 2-4 weeks later. At 3 weeks after exposure, 3 mg/L BaP significantly increased the rpsL mutant frequency (MF) in the gill and hepatopancreas by 5- and 2.3-fold, respectively, as compared to control fish. Sequence analysis showed that BaP mainly induced G:C to T:A and G:C to C:G transversions, which is consistent with the known mutagenic effects of BaP. In contrast, despite its extremely high mutagenic potency in Salmonella strains, PBTA-6 did not significantly increase the MF in the zebrafish gill or hepatopancreas. Although PBTA-6 is 300 times more mutagenic than BaP in the Ames test [T. Watanabe, H. Nukaya, Y. Terao, Y. Takahashi, A. Tada, T. Takamura, H. Sawanishi, T. Ohe, T. Hirayama, T. Sugimura, K. Wakabayashi, Synthesis of 2-phenylbenzotriazole-type mutagens, PBTA-5 and PBTA-6, and their detection in river water from Japan, Mutat. Res. 498 (2001) 107-115], calculation of the mutagenicity per mole of compound indicated that PBTA-6 was 33- and3.7-fold less mutagenic in the zebrafish gill and hepatopancreas, respectively, than BaP.
- Published
- 2008
9. In vivo mutagenesis in the lungs ofgpt-delta transgenic mice treated intratracheally with 1,6-dinitropyrene
- Author
-
Kenichi Masumura, Yasunobu Aoki, Kyoko Hiyoshi, Kimiko Amanuma, Hirohisa Takano, Akiko H. Hashimoto, and Takehiko Nohmi
- Subjects
Male ,Genetically modified mouse ,Hypoxanthine Phosphoribosyltransferase ,Epidemiology ,Health, Toxicology and Mutagenesis ,Mutant ,Mutagenesis (molecular biology technique) ,Mice, Transgenic ,chemical and pharmacologic phenomena ,Biology ,medicine.disease_cause ,complex mixtures ,Frameshift mutation ,Mice ,In vivo ,medicine ,Animals ,Nucleotide ,Lung ,Genetics (clinical) ,Genetics ,chemistry.chemical_classification ,Air Pollutants ,Mutation ,Pyrenes ,Sequence Analysis, DNA ,Molecular biology ,medicine.anatomical_structure ,chemistry ,Mutagenesis ,Mutagens - Abstract
1,6-Dinitropyrene (1,6-DNP) is a ubiquitous airborne pollutant found in diesel exhaust. In this study, mutagenesis was examined in the lungs of gpt-delta transgenic mice after intratracheal instillation of 0-0.1 mg 1,6-DNP. In addition, the 1,6-DNP-induced gpt mutation spectrum was compared with that of control mice. A single intratracheal injection of 0-0.05 mg 1,6-DNP resulted in significant dose-dependent increases in mutant frequency; the induced mutant frequency declined at the 0.1 mg dose. The average lung mutant frequencies at doses of 0.025, 0.05, and 0.1 mg 1,6-DNP were 2.9-, 4.1-, and 1.9-times higher than for control mice ((0.50+/-0.16)x10(-5)). The major mutations induced by 1,6-DNP included G:C-->A:T transitions, G:C-->T:A transversions, and 1-base deletions. Among the G:C-->A:T transitions isolated from 1,6-DNP-treated mice, five (at nucleotide positions 64, 110, 115, 116, and 418) were observed in four or more animals. These positions therefore are potential hotspots for 1,6-DNP mutation. The predominant frameshift mutations following 1,6-DNP treatment included single base pair deletions at G:C (9/13=69%). The results of this study indicate that 1,6-DNP is mutagenic for the lungs of mice.
- Published
- 2006
10. Frameshift mutations induced by the acridine mustard ICR-191 in embryos and in the adult gill and hepatopancreas of rpsL transgenic zebrafish
- Author
-
Takashi Nakamura, Yasunobu Aoki, and Kimiko Amanuma
- Subjects
Gills ,Embryo, Nonmammalian ,animal structures ,Sequence analysis ,animal diseases ,Health, Toxicology and Mutagenesis ,Mutant ,Hepatopancreas ,medicine.disease_cause ,Frameshift mutation ,Animals, Genetically Modified ,Genetics ,medicine ,Animals ,Frameshift Mutation ,Molecular Biology ,Zebrafish ,Mutation ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Mutagenesis ,Embryo ,biology.organism_classification ,Molecular biology ,Aminacrine ,Dose–response relationship ,Nitrogen Mustard Compounds ,Mutagens - Abstract
To determine whether frameshift mutations can be detected in rpsL transgenic zebrafish (Brachydanio rerio), embryos, and adult fish were treated with 6-chloro-9-[3-(2-chloroethylamino)-propylamino]-2-methoxyacridine (ICR-191). Embryos exposed to 0, 10, or 20 microM ICR-191 in a water bath for 18 h exhibited induced mutant frequencies (MFs) of 14 x 10(-5), 16 x 10(-5), and 25 x 10(-5), respectively. Only embryos exposed to 20 microM ICR-191 showed a significant increase in MF. The mutational spectra differed between the control and ICR-191-treated groups and single G:C pair insertions, which are a marked characteristic of ICR-191 mutagenesis, were observed in both 10 and 20 microM-treated embryos. In adult fish treated with 1 microM ICR-191 in a water bath for 18 h, a significant increase in MFs was observed in both gill (12 x 10(-5) and 44 x 10(-5) in control and treated fish, respectively), and hepatopancreas (5 x 10(-5) and 29 x 10(-5), respectively) 2 weeks after exposure. Sequence analysis showed that 58% of mutations in gill and 94% of mutations in hepatopancreas were single G:C pair insertions, which is typical of mutations induced by ICR-191. Additionally, these mutations occurred predominantly at a single site (CC sequence at bps 140-141) in the rpsL gene. Three weeks after exposure, however, the increased MFs and prominent mutational spectra of ICR-treated fish were undetectable. These findings suggest that using our protocols the rpsL transgenic zebrafish mutation assay is more effective for adult fish than for embryos, but that frameshift mutations can be detected in both embryos and adults at appropriate sampling times after treatment with ICR-191.
- Published
- 2005
11. In vivo mutagenesis induced by benzo[a]pyrene instilled into the lung ofgpt delta transgenic mice
- Author
-
Kimiko Amanuma, Yasunobu Aoki, Hirohisa Takano, Kyoko Hiyoshi, Akiko H. Hashimoto, Kenichi Masumura, and Takehiko Nohmi
- Subjects
Male ,Hypoxanthine Phosphoribosyltransferase ,Epidemiology ,Guanine ,Health, Toxicology and Mutagenesis ,Mutant ,Mutagenesis (molecular biology technique) ,Mice, Transgenic ,Biology ,medicine.disease_cause ,Mice ,chemistry.chemical_compound ,In vivo ,Benzo(a)pyrene ,Intubation, Intratracheal ,medicine ,Animals ,Thioguanine ,Transversion ,Base Pairing ,Lung ,Genetics (clinical) ,Genetics ,Air Pollutants ,Mutation ,Dose-Response Relationship, Drug ,Sequence Analysis, DNA ,Molecular biology ,Dose–response relationship ,chemistry ,Mutagenesis ,Mutagens - Abstract
Benzo[a]pyrene (B[a]P) is a ubiquitous airborne pollutant whose mutagenicity has been evaluated previously by oral and intraperitoneal administration to experimental animals. In this study, mutagenesis in the lungs, the target organ of air pollutants, was examined after a single intratracheal instillation of 0-2 mg B[a]P into gpt delta transgenic mice. Intratracheal injection of B[a]P resulted in a statistically significant and dose-dependent increase in gpt mutant frequency as measured by 6-thioguanine selection. The mutant frequencies at B[a]P doses of 0.5, 1, and 2 mg were 2.8, 4.2, and 6.8 times higher than the frequency seen in nontreated mice (0.60 +/- 0.13 x 10(-5)). The most frequent mutations induced by B[a]P treatment were G:C-->T:A transversions, which are characteristic of B[a]P mutagenesis in other models, and single-base deletions of G:C base pairs. To characterize the hotspots of B[a]P-induced mutations in the gpt gene, we analyzed sequences adjacent to the mutated G:C base pairs. Guanine bases centered in the nucleotide sequences CGT, CGA, and CGG were the most frequent targets of B[a]P. Our results indicate that intratracheal instillation of B[a]P into gpt delta mice causes a dose-dependent increase in gpt mutant frequency in the lung, and that the predominant mutation induced is G:C-->T:A transversion.
- Published
- 2005
12. Analytical Chemistry related to Biofunctional Research. Detection of environmental mutagens using transgenic animals
- Author
-
Yasunobu Aoki, Kimiko Amanuma, and Hiromi Sato
- Subjects
Chemistry ,Environmental chemistry ,Transgene ,Analytical Chemistry (journal) ,Analytical Chemistry - Abstract
大気や水環境中に存在する化学物質群が示す有害作用を検出するためのバイオアッセイは, 環境中の有害化学物質が人の健康に及ぼすリスクを包括的に評価するための新しい方法論である. 著者らは化学物質の変異原性に着目し, 変異原性モニター用の外来性遺伝子 (モニター遺伝子) を導入した動物を利用して, 環境中の化学物質が生体内で引き起こす突然変異を検出する手法を開発している. 著者らは, モニター遺伝子としてlac I 遺伝子をゲノムDNAに導入したBig Blueラットを用いてディーゼル排気の変異原性を評価した. その結果, 6mg/m3の粒子状物質を含むディーゼル排気は, ラット肺で変異原性を示すことが明らかになった. また著者らは, 水環境中に存在する変異原物質を検出するために, rpsL 遺伝子を導入した遺伝子導入ゼブラフィッシュ系統を確立した. この遺伝子導入魚の胚を用いて, エチルニトロソウレアやベンゾ[a]ピレンなどの変異原性を検出することができた. 遺伝子導入動物等の実験動物を用いた有害化学物質の環境モニタリングの可能性を議論する.
- Published
- 2002
13. [Topics from 'Overseas Drug Safety Information' in the past five years]
- Author
-
Kimiko, Amanuma
- Subjects
Time Factors ,Bone Density Conservation Agents ,Diphosphonates ,Codeine ,Angiogenesis Inhibitors ,Antibodies, Monoclonal, Humanized ,United States ,Bevacizumab ,Antitussive Agents ,Drug Information Services ,Product Surveillance, Postmarketing ,Adverse Drug Reaction Reporting Systems ,Humans ,Anticonvulsants ,United States Department of Agriculture ,Erythropoietin - Abstract
The Drug Safety Information Section of the Division of Safety Information on Drug, Food and Chemicals has been providing bulletins titled "Overseas Drug Safety Information" in Japanese since 2003. These bulletins comprise summarized and translated reports of important post-marketing drug safety information that are published by foreign regulatory agencies such as the US Food and Drug Administration (FDA) and the European Medical Agency. A new issue of the bulletin is posted every two weeks on the website of the National Institute of Health Sciences, Japan; to date (May 2013), a total of 280 issues have been posted, covering approximately 2400 foreign news items and articles since its inception. Recently, visits to the bulletin website have been increasing: the number of hits for each issue totaled 570,000 in fiscal 2012. Among the "Overseas Drug Safety Information" issued in the past five years, I briefly describe here several topics which interested me: erythropoietin-stimulating agents in chronic kidney disease and their cardiovascular risk; bisphosphonates and atypical femur fracture; effectiveness of oral liquid cough medicines containing codeine in children; bevacizumab for metastatic breast cancer; and congenital abnormality associated with the use of antiepileptic drugs by pregnant women. I also describe the potential safety signals identified by FDA using its Adverse Event Reporting System, and their importance in ensuring the safe use of drugs in the post-marketing phase.
- Published
- 2013
14. [Overseas Drug Safety Information 2008. Risk of infectious diseases associated with the use of immunosuppressive drugs]
- Author
-
Kimiko, Amanuma and Kaoru, Morikawa
- Subjects
Risk ,Drug-Related Side Effects and Adverse Reactions ,Tumor Necrosis Factor-alpha ,Drug Information Services ,Leukoencephalopathy, Progressive Multifocal ,Adverse Drug Reaction Reporting Systems ,Antibodies, Monoclonal ,Humans ,Communicable Diseases ,JC Virus ,Risk Assessment ,Immunosuppressive Agents - Published
- 2010
15. Hyaluronic acid synthesis is absent in normal human endothelial cells irrespective of hyaluronic acid synthetase inhibitor activity, but is significantly high in transformed cells
- Author
-
Youji Mitsui and Kimiko Amanuma
- Subjects
Cell ,Xenopus Proteins ,Biology ,Cell Fractionation ,Dermatan sulfate ,Acetylglucosamine ,Colony-Forming Units Assay ,Glycosaminoglycan ,chemistry.chemical_compound ,Transferases ,Glucosamine ,Hyaluronic acid ,medicine ,Humans ,Chondroitin sulfate ,Glucuronosyltransferase ,Hyaluronic Acid ,Molecular Biology ,Cells, Cultured ,Cell Line, Transformed ,Glycosaminoglycans ,Chondroitin Sulfates ,Glycosyltransferases ,Membrane Proteins ,Cell Biology ,Heparan sulfate ,Fibroblasts ,Endothelial stem cell ,medicine.anatomical_structure ,chemistry ,Biochemistry ,Endothelium, Vascular ,Heparitin Sulfate ,Hyaluronan Synthases ,Cell Division - Abstract
The characteristics of glycosaminoglycan (GAG) synthesis in normal and transformed human endothelial cells were analyzed by the incorporation of [ 3 H]glucosamine and by the activities of GAG synthetases. The GAG synthesized by normal endothelial cells consisted of mainly heparan sulfate (HS) and chondroitin sulfate/dermatan sulfate but little hyaluronic acid (HA) (less than 1%). The characteristics of GAG synthesis by normal cells reflected the synthetic enzyme activities for each individual GAG: the activity of HA synthetase was very low. In spite of this, the activity of HA synthetase inhibitor, induced in growth-retarded fibroblasts with low HA synthetase activity (Matuoka et al. (1987) J. Cell Biol., 104, 1105–1115), was very low in endothelial cells. In contrast to normal cells, transformed endothelial (ECV304) cells synthesized mainly HA (62% of total GAGs). These findings suggest that the regulatory system of GAG metabolism is cell type specific, and that transformation is accompanied by high levels of HA synthesis in endothelial cells.
- Published
- 1991
16. Mutations in the lungs of gpt delta transgenic mice following inhalation of diesel exhaust
- Author
-
Kimiko Amanuma, Hirohisa Takano, Akiko H. Hashimoto, Takehiko Nohmi, Sataro Goto, Rie Yanagisawa, Yoshiki Sugawara, Kenichi Masumura, Yasunobu Aoki, and Kyoko Hiyoshi
- Subjects
Hypoxanthine Phosphoribosyltransferase ,Diesel exhaust ,Epidemiology ,Guanine ,Health, Toxicology and Mutagenesis ,Mutant ,Mice, Transgenic ,complex mixtures ,Polymerase Chain Reaction ,Toxicology ,chemistry.chemical_compound ,Mice ,Animals ,Nucleotide ,Lung ,Genetics (clinical) ,Vehicle Emissions ,chemistry.chemical_classification ,Inhalation exposure ,Inhalation Exposure ,Inhalation ,Dose-Response Relationship, Drug ,Chemistry ,Mutagenesis ,respiratory system ,Molecular biology ,respiratory tract diseases ,Dose–response relationship ,Mutation - Abstract
Diesel exhaust (DE) is a major airborne pollutant of urban areas. It contains various polycyclic aromatic hydrocarbons (PAH) and nitrated PAHs. In this study, gpt delta mice were treated with inhalation of 1 or 3 mg m(-3) DE, or a single intratracheal instillation of diesel exhaust particles (DEP) or DEP extract. In the lungs of mice treated with inhalation of 3 mg m(-3) DE for 12 weeks, the mutant frequency (MF) was 3.2-fold higher than that of the control group (1.90 x 10(-5) and 0.59 x 10(-5), respectively). An instillation of DEP and DEP extract resulted in a significant dose-dependent linear increase in MF. In mice treated with 0.5 mg DEP and 0.2 mg DEP extract, the MFs were 3.0- and 2.7-fold higher than that of the control group, respectively. The mutagenic potency (MF mg(-1)) of DEP extract (5.6 x 10(-5)) was double that of DEP (2.7 x 10(-5)), suggesting that the mutagenicity of the latter is derived primarily from compounds in the extract, which itself is responsible for ca. 50% of the weight of DEP. G:C-->A:T transitions were the predominant gpt mutation induced by all three treatments and G:C-->T:A transversions were induced by DEP and DEP extract. Guanine bases centered in nucleotide sequences such as GGA, TGA, CGG, and CGT were the major mutation targets of all three treatments. Thus, our results suggest that the mutagens contained in DEP such as PAH and nitrated PAHs induce mutations and may be responsible for carcinogenesis caused by inhalation of DE.
- Published
- 2007
17. Enhanced spontaneous and benzo(a)pyrene-induced mutations in the lung of Nrf2-deficient gpt delta mice
- Author
-
Masayuki Yamamoto, Ken Itoh, Kimiko Amanuma, Hirohisa Takano, Yasunobu Aoki, Kyoko Hiyoshi, Michi Matsumoto, Kenichi Masumura, Akiko H. Hashimoto, and Takehiko Nohmi
- Subjects
Genetically modified mouse ,Male ,Cancer Research ,Hypoxanthine Phosphoribosyltransferase ,animal structures ,Ratón ,NF-E2-Related Factor 2 ,DNA Mutational Analysis ,Immunoblotting ,Biology ,medicine.disease_cause ,digestive system ,environment and public health ,Polymerase Chain Reaction ,chemistry.chemical_compound ,Mice ,In vivo ,Testis ,medicine ,Benzo(a)pyrene ,Animals ,Mutation frequency ,Lung ,Carcinogen ,Mice, Knockout ,Mutation ,Mutagenicity Tests ,respiratory system ,Molecular biology ,Oncology ,chemistry ,Liver ,Carcinogens ,Genotoxicity - Abstract
The lung is an organ that is sensitive to mutations induced by chemicals in ambient air, and transgenic mice harboring guanine phosphoribosyltransferase (gpt) gene as a target gene are a well-established model system for assessing genotoxicity in vivo. Transcription factor Nrf2 mediates inducible and constitutive expression of cytoprotective enzymes against xenobiotics and mutagens. To address whether Nrf2 is also involved in DNA protection, we generated nrf2+/−::gpt and nrf2−/−::gpt mice. The spontaneous mutation frequency of the gpt gene in the lung was approximately three times higher in nrf2-null (nrf2−/−) mice than nrf2 heterozygous (nrf2+/−) and wild-type (nrf2+/+) mice, whereas in the liver, the mutation frequency was higher in nrf2−/− and nrf2+/− mice than in nrf2+/+ wild-type mice. By contrast, no difference in mutation frequency was observed in testis among the three genotypes. A single intratracheal instillation of benzo(a)pyrene (BaP) increased the lung mutation frequency 3.1- and 6.1-fold in nrf2+/− and nrf2−/− mice, respectively, compared with BaP-untreated nrf2+/− mice, showing that nrf2−/− mice are more susceptible to genotoxic carcinogens. Surprisingly, mutation profiles of the gpt gene in BaP-treated nrf2+/− mice was substantially different from that in BaP-untreated nrf2−/− mice. In nrf2−/− mice, spontaneous and BaP-induced mutation hotspots were observed at nucleotides 64 and 140 of gpt, respectively. These results thus show that Nrf2 aids in the prevention of mutations in vivo and suggest that Nrf2 protects genomic DNA against certain types of mutations. [Cancer Res 2007;67(12):5643–8]
- Published
- 2007
18. MNNG-induced mutations in the adult gill and hepatopancreas and in embryos of rpsL transgenic zebrafish
- Author
-
Takashi Nakamura, Kimiko Amanuma, and Yasunobu Aoki
- Subjects
Genetics ,Gills ,Methylnitronitrosoguanidine ,biology ,Dose-Response Relationship, Drug ,Health, Toxicology and Mutagenesis ,Mutant ,Mutagenesis ,Hepatopancreas ,Embryo ,biology.organism_classification ,medicine.disease_cause ,Molecular biology ,Animals, Genetically Modified ,Transgenic zebrafish ,medicine ,Animals ,Molecular Biology ,Zebrafish ,Gene ,Genotoxicity ,Mutagens - Abstract
To evaluate the feasibility of a mutagenicity assay using adult rpsL transgenic zebrafish, 4- to 8-month-old females were exposed to N -methyl- N′ -nitro- N -nitrosoguanidine (MNNG) (0, 15 or 30 mg/L in a water bath for 2 h). At 2 weeks after exposure, MNNG showed a concentration-dependent significant increase in mutant frequency (MF) of 8 × 10 −5 , 18 × 10 −5 , and 51 × 10 −5 , respectively, in the gill. DNA sequencing revealed that 60–74% of the induced mutations were G:C to A:T transitions, consistent with the known mutagenic effects of MNNG. A marginal but significant increase in MF was observed in the hepatopancreas only in the group exposed to 30 mg/L, with the induction of some G:C to A:T transitions. A time-course of the appearance of mutations was determined in fish treated with 15 mg/L MNNG. In both, the gill and hepatopancreas, a higher MF was observed at 3 weeks than at 2 weeks, suggesting that an expression time of at least 3 weeks is preferable for the assay. When embryos (29 h post-fertilization) were exposed to MNNG (0, 50, and 150 mg/L) for 1 h, MFs increased significantly with an increase in the concentration of MNNG (5 × 10 −5 , 40 × 10 −5 , and 144 × 10 −5 , respectively) at 3 days after exposure. G:C to A:T transitions were the predominant mutations, and these occurred at the same sites in the rpsL gene as in adult tissues. Thus, MNNG induces typical mutations in the gill and hepatopancreas of adult fish, and in embryos, suggesting that the rpsL zebrafish is a useful tool for monitoring genotoxicity caused by water-borne mutagens.
- Published
- 2004
19. Mutational spectra of benzo[a]pyrene and MeIQx in rpsL transgenic zebrafish embryos
- Author
-
Tadayoshi Shigeoka, Hotaka Saito, Yasunobu Aoki, Suguru Tone, and Kimiko Amanuma
- Subjects
Genetics ,Ribosomal Proteins ,Mutation ,Mutation Spectra ,Base pair ,Health, Toxicology and Mutagenesis ,Mutant ,Embryo ,Biology ,medicine.disease_cause ,Molecular biology ,Animals, Genetically Modified ,chemistry.chemical_compound ,Quinoxaline ,chemistry ,Benzo(a)pyrene ,Quinoxalines ,medicine ,Pyrene ,Animals ,Zebrafish ,Mutagens - Abstract
To evaluate the rpsL transgenic zebrafish ( Brachydanio rerio ) mutation assay, we treated the embryos with benzo[a]pyrene (B[a]P) (10 μg/ml) or 2-amino-3,8-dimethylimidazo[4,5- f ]quinoxaline (MeIQx) (300 μg/ml) for 16 h and determined the mutation spectra. These treatments were previously reported to induce mutant frequencies that were 4.3 and 2.4 times the control value, respectively. In the B[a]P-treated group, half of the mutations were single base substitutions, 74% of which occurred at G:C base pairs. Among G:C base pair substitutions, G:C to T:A and G: C to C:G transversions were predominant, suggesting that B[a]P induced mutations in zebrafish embryos by mechanisms previously described in mammalian tissues. In the MeIQx-treated group, about 60% of the mutations were deletions. Some specific mutations were found, but the compound primarily amplified the background mutation level; improvement in the conditions of treatment may be required for elucidating MeIQx-mutagenesis in this system. This study showed that transgenic zebrafish may be a useful tool for detecting mutagens in aquatic environments and for elucidating mutagenic mechanisms.
- Published
- 2001
20. Transgenic zebrafish for detecting mutations caused by compounds in aquatic environments
- Author
-
Hiroyuki Takeda, Hiroshi Amanuma, Yasunobu Aoki, and Kimiko Amanuma
- Subjects
Male ,Transgene ,DNA Mutational Analysis ,Genetic Vectors ,Biomedical Engineering ,Gene Dosage ,Mutagenesis (molecular biology technique) ,Bioengineering ,Biology ,medicine.disease_cause ,Applied Microbiology and Biotechnology ,Gene dosage ,Animals, Genetically Modified ,Plasmid ,Shuttle vector ,Quinoxalines ,medicine ,Benzo(a)pyrene ,Animals ,Transgenes ,Mutation frequency ,Gene ,Zebrafish ,Genetics ,Mutation ,Dose-Response Relationship, Drug ,Mutagenicity Tests ,Ribosomal Protein S9 ,Escherichia coli Proteins ,Molecular biology ,Mutagenesis ,Ethylnitrosourea ,Molecular Medicine ,Female ,Water Pollutants, Chemical ,Biotechnology ,Mutagens - Abstract
We have established a transgenic zebrafish line carrying a shuttle vector plasmid (pML4) for detecting mutagens in aquatic environments. The plasmid contains the rpsL gene of Escherichia coli as a mutational target gene, and the kanamycin-resistance gene for recovering the plasmid from the chromosomal DNA. To evaluate the system, we treated embryos of the transgenic fish with N-ethyl-N-nitrosourea (ENU), which induces a dose-dependent increase in the mutation frequency of the target gene. The mutation spectrum was consistent with the proposed mechanism of ENU mutagenesis. Similarly, treating the embryos with benzo[a]pyrene or 2-amino-3, 8-dimethylimidazo[4,5- f]quinoxaline, which are found in naturally polluted water, significantly increased the frequency of mutations in the target gene.
- Published
- 2000
21. Overexpression of MP41 gene in a transformed endothelial cell line correlates with the increased fibronectin expression and a decreased incidence of tumorigenicity
- Author
-
Motoo Watanabe, Shuichi Oka, Kimiko Amanuma, Masaaki Kondo, and Norio Ishida
- Subjects
Time Factors ,Cdc25 ,Cell ,Transplantation, Heterologous ,Biophysics ,Gene Expression ,Mice, Nude ,Biology ,Transfection ,Biochemistry ,Cell Line ,Mice ,Cell Movement ,Complementary DNA ,medicine ,Animals ,Humans ,RNA, Messenger ,Molecular Biology ,Gene ,Cell Line, Transformed ,Proteins ,Cell Biology ,Neoplasms, Experimental ,Molecular biology ,Recombinant Proteins ,Cell biology ,Circadian Rhythm ,Fibronectins ,Endothelial stem cell ,Fibronectin ,Transformation (genetics) ,Kinetics ,medicine.anatomical_structure ,Cell Transformation, Neoplastic ,Protein Biosynthesis ,biology.protein ,Endothelium, Vascular ,Cell Division - Abstract
mp41 gene, which was originally identified as a gene regulated by the circadian clock, showed some similarity with yeast cell cycle regulator, CDC25, and its mRNA expression is restricted mainly to non-dividing cell. To elucidate the growth regulatory of mp41, mp41 cDNA was transfected into a transformed human endothelial cell line. All stable mp41 transformants showed increased levels of fibronectin expression and reduced migratory activityin vitro. Although thein vitrogrowth rate of mp41 transformants and their ability to grow in soft agar were not significantly altered, their tumor formation was suppressed significantly in nude mice. The results imply that mp41 gene overexpression altered the tumorigenicity associated with fibronectin elevation in stable transformation of the transformed endothelial cell line.
- Published
- 1996
22. In vivo mutagenesis in the lungs of gpt‐delta transgenic mice treated intratracheally with 1,6‐dinitropyrene.
- Author
-
Akiko H. Hashimoto, Kimiko Amanuma, Kyoko Hiyoshi, Hirohisa Takano, Ken‐ichi Masumura, Takehiko Nohmi, and Yasunobu Aoki
- Published
- 2006
23. In vivo mutagenesis induced by benzo[a]pyrene instilled into the lung of gpt delta transgenic mice.
- Author
-
Akiko H. Hashimoto, Kimiko Amanuma, Kyoko Hiyoshi, Hirohisa Takano, Ken‐ichi Masumura, Takehiko Nohmi, and Yasunobu Aoki
- Published
- 2005
24. Characterization of Lysosomal Acid Lipase Purified from Rabbit Liver1
- Author
-
Tsuneo Imanaka, Shoji Ohkuma, Kimiko Amanuma-Muto, and Tatsuya Takano
- Subjects
Gel electrophoresis ,Chromatography ,biology ,Size-exclusion chromatography ,General Medicine ,Biochemistry ,Sepharose ,Gel permeation chromatography ,chemistry.chemical_compound ,Isoelectric point ,chemistry ,biology.protein ,Sodium dodecyl sulfate ,Lipase ,Molecular Biology ,Polyacrylamide gel electrophoresis - Abstract
Lysosomal acid lipase from rabbit liver was solubilized with digitonin and purified 25,000-fold by Bio-Gel A-1.5 m, DEAE Bio-Gel A and phenyl Sepharose column chromatographies, preparative slab gel electrophoresis and finally Affi-Gel Blue affinity column chromatography. The purified enzyme gave a single protein band on polyacrylamide gel electrophoresis both in the presence and absence of sodium dodecyl sulfate. The molecular weight of the acid lipase was estimated to be 42,000 by sodium dodecyl sulfate polyacrylamide gel electrophoresis and 40,000 by gel filtration on Bio-Gel A-0.5 m. The enzyme was a hydrophobic glycoprotein with an isoelectric point of 5.15-5.90. The purified enzyme hydrolyzed tri-, di-, and monoolein and cholesterol oleate, with apparent Vmax values of 5.41, 56.1, 21.7, and 3.25 mumol/min/mg protein, and Km values of 50, 70, 200, and 40 microM, respectively. It hydrolyzed 4-methylumbelliferyl esters with fatty acids of different lengths in the order, medium length chains greater than long chains much greater than short chains. It did not hydrolyze dipalmitoylphosphatidylcholine. Its activity was inhibited by micromolar concentrations of p-chloromercuriphenyl sulfonic acid and p-bromophenacyl bromide and millimolar concentrations of Cu2+ and diethylpyrocarbonate. The activities of the enzyme towards the five substrates listed above showed almost identical thermal stabilities, mobilities on polyacrylamide gel electrophoresis and inhibition by several inhibitors. These findings support the idea that one enzyme is involved in the hydrolysis of both acylglycerols and cholesterol esters in lysosomes.
- Published
- 1984
25. Some Remarks on the Initiation of Atherosclerosis
- Author
-
Shoji Ohkuma, Tatsuya Takano, Kimiko Amanuma, and Toku Kanaseki
- Published
- 1984
26. Effects of Phospholipids on Lysosomal Acid Lipase Purified from Rabbit Liver1
- Author
-
Tatsuya Takano, Kimiko Amanuma-Muto, Tsuneo Imanaka, and Shoji Ohkuma
- Subjects
chemistry.chemical_classification ,Phosphatidylethanolamine ,Degree of unsaturation ,Chromatography ,Double bond ,biology ,General Medicine ,Phosphatidylserine ,Biochemistry ,Enzyme assay ,chemistry.chemical_compound ,chemistry ,Phosphatidylcholine ,Cardiolipin ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Phosphatidylinositol ,Molecular Biology - Abstract
The effects of phospholipids on lysosomal acid lipase purified from rabbit liver were studied. Non-ionic phospholipids such as phosphatidylethanolamine and phosphatidylcholine increased the enzyme activity. However, anionic phospholipids such as phosphatidylserine, phosphatidylinositol, and cardiolipin were ineffective. The acyl chain length and the degree of unsaturation of synthetic phospholipids were also related to the enzyme activity. Among a series of saturated phosphatidylcholines with different acyl chain lengths, 1,2-dipalmitoyl-sn-glycero-3-phosphorylcholine was the most effective. Among a series of unsaturated phosphatidylcholines, the enzyme activity increased in parallel with the number of double bonds. The role of lysosomal acid lipase in relation to phospholipids is discussed.
- Published
- 1983
27. Involvement of Lysosomal Phospholipid and its Polyunsaturated Fatty Acid in Accumulation of Cholesterol Ester in Atherosclerosis
- Author
-
Shoji Ohkuma, Kimiko Amanuma, Tsuneo Imanaka, Masayasu Enomoto, Tatsuya Takano, and Hiroko Takahashi
- Subjects
chemistry.chemical_classification ,chemistry.chemical_compound ,chemistry ,Biochemistry ,Cholesterol ,Phospholipid ,Polyunsaturated fatty acid - Published
- 1987
28. Cinemicrophotographic observation of aortic foam cells containing anisotropic lipid inclusions
- Author
-
Tsuneo Imanaka, Shoji Ohkuma, Kimiko Amanuma-Muto, and Tatsuya Takano
- Subjects
Microphotography ,Aorta ,Pathology ,medicine.medical_specialty ,Histology ,Materials science ,Physiology ,medicine.artery ,medicine ,Cell Biology ,Anatomy ,Biochemistry ,Pathology and Forensic Medicine - Published
- 1984
29. Esterastin: A Potent Inhibitor of Lysosomal Acid Lipase1
- Author
-
Gnobor G. Ecsedi, Tsuneo Imanaka, Yoshinori Moriyama, Takaaki Aoyagi, Kimiko Amanuma-Muto, Tatsuya Takano, and Shoji Ohkuma
- Subjects
chemistry.chemical_classification ,biology ,Substrate (chemistry) ,Lysosomal Acid Lipase ,General Medicine ,Esterastin ,Biochemistry ,Enzyme assay ,Carboxylesterase ,Enzyme ,chemistry ,biology.protein ,Molecular Biology ,Acid lipase ,IC50 - Abstract
The effect of a fungal metabolite, esterastin, on lysosomal acid lipase purified from rabbit liver was studied. Esterastin inhibited the enzyme activity very strongly (IC50, about 80 nM). The inhibition of acid lipase by esterastin was competitive with respect to the substrate and the inhibition constant for esterastin was 90 nM. Esterastin was less inhibitory to other lipolytic enzymes, such as pancreatic lipase and carboxylesterase. Thus esterastin is a potent new inhibitor of lysosomal acid lipase.
- Published
- 1983
30. Studies on fine structure and location of lipids in quick-freeze replicas of atherosclerotic aorta of WHHL rabbits
- Author
-
Toku Kanaseki, Yohko Ikeuchi, Shoji Ohkuma, Kimiko Amanuma, and Tatsuya Takano
- Subjects
Male ,Arteriosclerosis ,Aortic Diseases ,Aorta, Thoracic ,Pathology and Forensic Medicine ,Lipid droplet ,medicine.artery ,medicine ,Extracellular ,Animals ,Quick Freeze ,Lamellar structure ,Molecular Biology ,Foam cell ,Aorta ,Freeze Etching ,Chemistry ,technology, industry, and agriculture ,Cell Biology ,General Medicine ,Lipids ,Extracellular Matrix ,Microscopy, Electron ,Membrane ,Biochemistry ,Microscopy, Electron, Scanning ,Biophysics ,lipids (amino acids, peptides, and proteins) ,Rabbits ,Extracellular Space ,Intracellular ,Foam Cells - Abstract
The fine structure of intracellular and extracellular lipids in the atherosclerotic aorta of Watanabe-heritable hyperlipidemic (WHHL) rabbits was demonstrated by a quick-freeze etching technique. Many lipid droplets, with and without a membrane, were observed in the foam cells. Membrane-free droplets were observed as onion-like structure with a concentric lamellar structure surrounded by 10 nm filaments. Droplets surrounded by a limited membrane probably correspond to lipid-laden lysosomes. In the extracellular connective tissue space, marked accumulation of lipids with a vesicular structure was seen among collagen fibers. The appearance of these lipids was similar to that of lipids in lysosomes of foam cells.
- Published
- 1987
31. Effect of intratracheal instillation of cadmium chloride on phospholipids in alveolar wash fluid
- Author
-
Kazuo T. Suzuki and Kimiko Amanuma
- Subjects
Male ,medicine.medical_treatment ,Phospholipid ,chemistry.chemical_element ,Cadmium chloride ,Toxicology ,chemistry.chemical_compound ,Cadmium Chloride ,Pulmonary surfactant ,Phosphatidylcholine ,medicine ,Animals ,Therapeutic Irrigation ,Saline ,Phospholipids ,Cadmium ,Lung ,Chromatography ,Fatty Acids ,Pulmonary Surfactants ,Rats, Inbred Strains ,Organ Size ,Rats ,Pulmonary Alveoli ,Trachea ,medicine.anatomical_structure ,chemistry ,Biochemistry ,Phosphatidylcholines ,Pulmonary alveolus - Abstract
The effect of cadmium chloride on phospholipids in the alveolar wash fluid was investigated by instilling the chemical (2.5 μg Cd/0.4 ml saline per rat) into rat trachea. Two days later the phospholipid content of the was fluid increased markedly in the cadmium-treated group to about 2.4 times that in the control (saline-treated) group. The relative amount of phosphatidylcholine and the fatty acid composition of phosphatidylcholine were not altered by the cadmium treatment, and retained a composition typical of lung surfactant. These findings suggest that cadmium induces a marked increase in surfactant phospholipids in the lung at a very low dose.
- Published
- 1987
32. Electron Microscopic Observation of Lipid Droplets in Foam Cells of WHHL Rabbit Atheromatous Aorta
- Author
-
Kimiko Amanuma, Tsuneo Imanaka, Toku Kanaseki, and Tatsuya Takano
- Subjects
Aorta ,Quick freezing ,Chemistry ,medicine.artery ,Lipid droplet ,medicine ,Biophysics ,Rabbit (nuclear engineering) ,Anatomy ,Electron microscopic - Published
- 1985
33. Monoclonal antibodies recognizing lipid-laden cells and extracellular regions with lipid-deposits in atherosclerotic aorta
- Author
-
Tatsuya Takano, Kimiko Amanuma, Keiji Nakagami, Yoji Yoshida, Shoji Ohkuma, and Junji Kimura
- Subjects
Pathology ,medicine.medical_specialty ,medicine.drug_class ,Arteriosclerosis ,Aminopterin ,Monoclonal antibody ,Pathology and Forensic Medicine ,Extracellular matrix ,medicine ,Extracellular ,Animals ,Molecular Biology ,Foam cell ,Hybridomas ,biology ,Macrophages ,Antibodies, Monoclonal ,Cell Biology ,General Medicine ,Lipid Metabolism ,Lipids ,Extracellular Matrix ,biology.protein ,Immunohistochemistry ,Female ,Rabbits ,Antibody ,Clone (B-cell biology) ,medicine.drug ,Foam Cells - Abstract
Monoclonal antibodies against lipid-laden cells and against extracellular regions of lipid-deposits in atherosclerotic aorta were prepared. Mice were immunized with a delipidated homogenate of atherosclerotic aorta of Watanabe-heritable hyperlipidemic rabbits. Hybridomas were obtained by fusion and cultured in hypoxanthine, aminopterin and thymidine selection medium. Specific antibodies were selected by indirect immunohistochemical staining of frozen sections of atherosclerotic aorta. Nine clones that produced antibodies that stained the atherosclerotic intima exclusively were selected and cloned by limiting dilution. Finally two clones (FCR1a/201F, FCR1b/ 904B) producing antibodies specific to lipid-laden cells and one clone (EMR1a/212D) producing an antibody specific to regions with lipid deposits in the extracellular matrix were established. These monoclonal antibodies may help in understanding how lipids accumulate in atherosclerosis.
- Published
- 1986
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.