DOSE-THRESHOLD FOR THYROID TUMOR-PROMOTING EFFECTS OF ORALLY AMINISTERED KOJIC ACID IN RATS AFTER INITIATION WITH N-bis(2-HYDROXYPROPYL) NITROSAMINE
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概要
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In order to evaluate the threshold dose of thyroid tumor-promoting effects of KA, male F344 rats were initiated with N-bis(2-hydroxypropyl) nitrosamine (DHPN; 2000 mg/kg body wt, single s.c. injection) and, starting 1 week later, received pulverized basal diet containing 0%, 0.002%, 0.008%, 0.03%, 0.125%, 0.5% or 2%KA for 20 weeks. Five rats each in the 0%, 0.125%, 0.5% and 2%KA groups were sacrificed at week 12, and 10 rats each in all groups at week 20. As an additional experiment, three groups without DHPN initiation received basal diet, a diet containing 0.5% or 2%KA for 20 weeks. The serum T4 levels were significantly decreased in the DHPN-initiated groups given 0.125%KA or more at week 12. No significant decreases in serum T3 levels were observed in the groups treated with DHPN+KA and a significant increase was evident in the 2%KA-alone group at week 20. Some rats in the DHPN+2%KA group at weeks 12 and 20 and the 2%KA-alone group at week 20 showed pronounced elevation of serum TSH. Thyroid weights were significantly increased in the DHPN-initiated groups receiving 0.5% and 2%KA at weeks 12 and 20 and in the 2%KA-alone group at week 20. Histopathologically, the incidences of focal thyroid follicular cell hyperplasias in the DHPN-initiated groups treated with 0.125%, 0.5% and 2%KA at week 20 were 5/10, 10/10 and 8/8 rats, respectively. At week 20, adenomas were observed in 7/10 rats in the DHPN+0.5% KA group and 8/8 rats in the DHPN+2%KA group, and carcinomas were observed in 6/8 rats in the DHPN+2%KA group. In the groups without DHPN initiation, only focal follicular cell hyperplasia was observed in 1/9 rats in the 2%KA-alone group. These results suggest that the no-observed-adverse effect for the thyroid tumor-promoting effect of KA is 0.03%(15.5 mg/kg/day) under the present experimental conditions, and that KA possesses weak tumorigenic activity in rats due to continuous serum TSH stimulation by a non-genotoxic mechanism.
- 日本トキシコロジー学会の論文
- 2001-05-21
著者
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Hirose Masao
Division of Pathology, National Institute of Health Sciences
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ONODERA Hiroshi
Division of Pathology, National Institute of Health Sciences
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FUJIMOTO Nariaki
Department of Cancer Research, Hiroshima University
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Yasuhara K
Division Of Pathology National Institute Of Health Sciences
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Yasuhara Kazuo
Divisions Of Toxicology National Institute Of Hygienic Sciences
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Yasuhara Kazuo
Division Of Pathology National Institute Of Health Sciences
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TAKAGI Hisayoshi
Division of Pathology, National Institute of Health Sciences
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TAMURA Toru
Division of Pathology, National Institute of Health Sciences
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MITSUMORI Kunitoshi
Division of Pathology, National Institute of Health Sciences
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Takizawa Tamotsu
東京農工大学
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Takizawa Tamotsu
Division Of Pathology National Institute Of Health
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Takizawa Tamotsu
Division Of Pathology National Institute Of Health Sciences
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Hirose Masao
国立医薬品食品衛生研究所 病理
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Takegawa Kiyoshi
Division of Pathology, National Institute of Health Sciences
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Tamura Toru
Division Of Pathology National Institute Of Health Sciences
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Takagi Hisayoshi
国立医薬品食品衛生研究所
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Takagi Hisayoshi
Division Of Pathology National Institute Of Health Sciences
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Onodera Hiroshi
東京都健康安全研究センター
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小野寺 博志
Division Of Pathology National Institute Of Health Sciences
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Onodera Hiroshi
Pharmaceuticals And Medical Devices Agency
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Tamura Tomohide
Medical Oncology Division National Cancer Center Hospital
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Takegawa K
Division Of Pathology National Institute Of Health Sciences:safety Evaluation Drug Development Labor
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Takegawa Kiyoshi
三菱ウェルファーマ
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Takada Koichi
Safety Evaluation Laboratory Yoshitomi Pharmaceutical Industries Co. Ltd.
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Takegawa K
Toxicology Laboratories Pharmaceutical Research Division Mitsubishi Pharma Corporation
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Takegawa Kiyoshi
Department Of Pathology National Institute Of Health Sciences
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Takegawa Kiyoshi
Safety Evaluation Drug Development Laboratories Pharmaceutical Research Division Yoshitomi Pharmaceu
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Kodama Yukio
Division Of Pathology National Institute Of Health Sciences
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FURUNO Nobuaki
Institute for Amphibian Biology, Graduate School of Science, Hiroshima University
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Kitamura Y
Division Of Pathology National Institute Of Health Sciences
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Takada Koichi
国立医薬品食品衛生研究所
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安原 加壽雄
San-ei Gen F.f.i. Inc.
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Furuno Nobuaki
Institute For Amphibian Biology Graduate School Of Science Hiroshima University
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Kurokawa Y
Division Of Toxicology National Institute Of Health Sciences
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Hirose Masao
Division Of Pathology National Institute Of Health Sciences
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Hirose Masao
Div. Pathol. Natl. Inst. Htlh. Sci.
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Mitsumori Kunitoshi
Division Of Pathology National Institute Of Health Sciences
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Takada Koichi
Division Of Toxicology Biological Safety Research Center National Institute Of Health Sciences
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Fujimoto Nariaki
Research Institute For Radiation Biology And Medicine Hiroshima University
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Fujimoto Nariaki
Department Of Cancer Research Institute Of Radiation Biology And Medicine Hiroshima University
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Takada Koichi
Dept. Of Toxicology Bioological Safety Research Center National Institute Of Hygienic Sciences
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Kamimura Yasuhiro
Safety Evaluation Lab. Yoshitomi Pharm.
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Onodera H
Pharmaceuticals And Medical Devices Agency
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Takada Kouichi
Division Of Toxicology Biological Safety Research Center National Institute Of Health Sciences
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三森 国敏
Division Of Pathology National Institute Of Health Sciences
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Fujimoto N
Research Institute For Radiation Biology And Medicine Hiroshima University
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Kashida Y
Laboratory Of Veterinary Pathology Tokyo University Of Agriculture And Technology
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Kodama Yukio
Cel. Mol. Tox. Div. Nihs
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Matsumoto K
Laboratory Of Veterinary Pathology Tokyo University Of Agriculture And Technology
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Takada Koichi
Divisions Of Toxicology National Institute Of Hygienic Sciences
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Onodera Hiroshi
Dvision Of Pathology Biological Safety Research Center National Institute Of Health Sciences
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Yasuhara Kazuo
Division Of Medicinal Chemistry And Pharmacognosy Ohio State University
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Takada Koichi
Division Of Toxicology Biological Safety Research Center National Institute Of Hygienic Sciences
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Takada Koichi
吉富製薬福崎安全性研究所
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Tamura Toru
Division Of Pathology National Institute Of Health
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