Phillips David H, Hewer Alan, Osborne Martin R, Cole Kathleen J, Churchill Cyd, Arlt Volker M
Institute of Cancer Research, Brookes Lawley Building, Cotswold Road, Sutton SM2 5NG, UK.
Mutagenesis. 2005 Jul;20(4):297-303. doi: 10.1093/mutage/gei038. Epub 2005 May 31.
Tamoxifen is an anti-oestrogen widely used in the adjuvant therapy of breast cancer and is also used as a prophylactic to prevent the disease in high-risk women. An increased risk of endometrial cancer has been observed in both settings. In rats, tamoxifen potently induces liver carcinomas and also induces uterine tumours when given neonatally. It forms DNA adducts in rat liver via the formation of alpha-hydroxytamoxifen, the ultimately reactive form being generated by sulfotransferase. In order to investigate the formation of tamoxifen-derived DNA adducts in other rat tissues, female Fischer F344 or Sprague-Dawley rats were treated with tamoxifen or alpha-hydroxytamoxifen by gavage or by intraperitoneal injection, daily for 1, 4 or 7 days, and DNA adducts were detected by (32)P-postlabelling analysis. Tamoxifen formed DNA adducts in the liver but not in other tissues (uterus, stomach, kidney, spleen and colon). alpha-Hydroxytamoxifen also formed adducts at high levels in liver, but with the exception of single animals (1/8) in which a low level of adducts was detected in the stomach in one case, and in the kidney in the other; it also did not give rise to adducts in other tissues. The results suggest that tamoxifen is a genotoxic carcinogen in rat liver, but a non-genotoxic carcinogen in rat uterus, making it, uniquely, a carcinogen with more than one mechanism of action. Mutagenicity experiments conducted in Salmonella typhimurium strains expressing bacterial or human N,O-acetyltransferase did not provide evidence that either alpha-hydroxytamoxifen or alpha-hydroxy-N-desmethyltamoxifen undergoes metabolic activation by acetylation. The confinement of ST2A2, the isozyme of hydroxysteroid sulfotransferase that can activate the compounds, mainly to rat liver is the possible reason for the formation of ducts in the liver but not in other organs of the rat.
他莫昔芬是一种抗雌激素药物，广泛用于乳腺癌的辅助治疗，也用作预防高危女性患该病的预防药物。在这两种情况下都观察到子宫内膜癌风险增加。在大鼠中，他莫昔芬能有效诱发肝癌，新生大鼠给予该药物时还会诱发子宫肿瘤。它通过形成α-羟基他莫昔芬在大鼠肝脏中形成DNA加合物，最终的活性形式由磺基转移酶产生。为了研究他莫昔芬衍生的DNA加合物在大鼠其他组织中的形成情况，对雌性Fischer F344或Sprague-Dawley大鼠通过灌胃或腹腔注射给予他莫昔芬或α-羟基他莫昔芬，每天1次、4次或7次，然后通过³²P后标记分析检测DNA加合物。他莫昔芬在肝脏中形成DNA加合物，但在其他组织（子宫、胃、肾、脾和结肠）中未形成。α-羟基他莫昔芬在肝脏中也大量形成加合物，但有个别动物除外（8只中有1只），其中1例在胃中检测到低水平加合物，另1例在肾中检测到；它在其他组织中也未产生加合物。结果表明，他莫昔芬在大鼠肝脏中是一种遗传毒性致癌物，但在大鼠子宫中是一种非遗传毒性致癌物，这使其独特地成为一种具有多种作用机制的致癌物。在表达细菌或人N,O-乙酰转移酶的鼠伤寒沙门氏菌菌株中进行的致突变性实验没有提供证据表明α-羟基他莫昔芬或α-羟基-N-去甲基他莫昔芬通过乙酰化进行代谢活化。羟基类固醇磺基转移酶的同工酶ST2A2主要局限于大鼠肝脏，该同工酶可激活这些化合物，这可能是在大鼠肝脏而非其他器官中形成导管的原因。
