DNA damage and altered gene expression of enzymes for metabolism and DNA repair by tamoxifen and toremifene in the female rat liver.
DNA damage and altered gene expression of enzymes for metabolism and DNA repair by tamoxifen and toremifene in the female rat liver.
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他莫昔芬和托瑞米芬对雌性大鼠肝脏中的 DNA 损伤以及新陈代谢和 DNA 修复酶的基因表达的改变。
DOI：
10.1111/j.1349-7006.2006.00211.x
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Degawa,Masakuni
中科院分区：
文献类型：
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作者：
Hashiba,Masamichi;Kasahara,Toshihiko;Kim,SungYeon;Shibutani,Shinya;Degawa,Masakuni
以雌性SD大鼠为模型，比较研究了致癌药物和非致癌药物TOR对大鼠肝脏DNA加合物形成及肝脏药物代谢酶和DNA修复酶/蛋白基因表达的影响。或TOR(40毫克/公斤/天，I.G.)持续1、2或8周。两种剂量的给药1周后仍可形成肝组织DNA加合物，且加合物水平随剂量和治疗时间的延长而增加，而TOR组大鼠肝组织中未检测到DNA加合物。相反，和TOR在增加负责代谢激活和解毒的药物代谢酶的基因表达方面表现出几乎相同的能力，至少达到了2周的治疗标志。因此，组和TOR组大鼠之间DNA加合物形成的差异不会主要依赖于诱导肝脏药物代谢酶的能力。此外，治疗8周后，细胞色素P4503A2(细胞色素P4503A2)的基因表达显著增加，可能是导致DNA加合物形成增加的原因之一。在任何一种药物治疗的大鼠中，负责核苷酸切除修复系统的DNA修复酶/蛋白质的基因表达都没有显著变化。本研究结果提示，和TOR在致癌活性上的差异取决于DNA加合物的形成能力，而不是调节药物代谢酶和DNA修复酶/蛋白的表达。(癌症科学2006；97：468- 477)
Effects of hepatocarcinogenic TAM and non‐hepatocarcinogenic TOR on the formation of hepatic DNA adducts and on the gene expression of hepatic drug‐metabolizing enzymes and DNA repair enzymes/proteins were comparatively examined in female Sprague‐Dawley rats treated with TAM (20 or 40 mg/kg/day, i.g.) or TOR (40 mg/kg/day, i.g.) for 1, 2 or 8 weeks. Hepatic TAM‐DNA adducts were formed even after 1 week of treatment with TAM at either dose, and the adduct levels increased in a dose‐ and treatment period‐dependent manner, whereas no DNA adducts were detected in any of the TOR‐treated rats. Conversely, TAM and TOR showed almost the same capacity for increasing the gene expression of drug‐metabolizing enzymes responsible for metabolic activation and detoxification, at least up to the 2‐week treatment mark. Accordingly, differences in DNA adduct formation between TAM‐ and TOR‐treated rats would not be primarily dependent on the capacity for inducing hepatic drug‐metabolizing enzymes. In addition, a drastic increase in the gene expression of cytochrome P4503A2 (CYP3A2), an activation enzyme of TAM, by the 8‐week treatment with TAM might have contributed to the increased formation of DNA adducts. Gene expressions of DNA repair enzymes/proteins responsible for a nucleotide excision repair system were not significantly changed in any of the rats treated with either drug. The present findings suggest that the difference between TAM and TOR in hepatocarcinogenic potency is dependent on the capacity to form DNA adducts rather than modulating the expression of drug‐metabolizing enzymes and DNA repair enzymes/proteins. (Cancer Sci2006; 97: 468– 477)