Tamura T, Mitsumori K, Onodera H, Fujimoto N, Yasuhara K, Takegawa K, Takagi H, Hirose M
Division of Pathology, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
J Toxicol Sci. 2001 May;26(2):85-94. doi: 10.2131/jts.26.85.
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.
为了评估卡必醇（KA）促进甲状腺肿瘤的阈剂量，对雄性F344大鼠皮下注射N - 双（2 - 羟丙基）亚硝胺（DHPN；2000 mg/kg体重，单次注射）进行启动处理，1周后开始给予含0%、0.002%、0.008%、0.03%、0.125%、0.5%或2%KA的粉状基础饲料，持续20周。在第12周时，处死0%、0.125%、0.5%和2%KA组各5只大鼠，在第20周时，处死所有组各10只大鼠。作为一项额外实验，对三组未用DHPN启动的大鼠给予基础饲料、含0.5%或2%KA的饲料，持续20周。在第12周时，给予0.125%KA及以上剂量的经DHPN启动的组中，血清T4水平显著降低。在用DHPN + KA处理的组中，未观察到血清T3水平有显著降低，且在第20周时，单独给予2%KA的组血清T3水平明显升高。在第12周和20周时，DHPN + 2%KA组的一些大鼠以及在第20周时单独给予2%KA组的一些大鼠血清TSH明显升高。在第12周和20周时，接受0.5%和2%KA的经DHPN启动的组以及在第20周时单独给予2%KA的组甲状腺重量显著增加。组织病理学检查显示，在第20周时，用0.125%、0.5%和2%KA处理的经DHPN启动的组中，局灶性甲状腺滤泡细胞增生的发生率分别为5/10、10/10和8/8只大鼠。在第20周时，在DHPN + 0.5%KA组的10只大鼠中有7只观察到腺瘤，在DHPN + 2%KA组的8只大鼠中均观察到腺瘤，在DHPN + 2%KA组的8只大鼠中有6只观察到癌。在未用DHPN启动的组中，仅在单独给予2%KA组的9只大鼠中有1只观察到局灶性滤泡细胞增生。这些结果表明，在当前实验条件下，KA促进甲状腺肿瘤的未观察到不良反应的剂量为0.03%（15.5 mg/kg/天），并且由于非遗传毒性机制导致血清TSH持续刺激，KA在大鼠中具有弱致癌活性。
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