Heres-Pulido M Eugenia, Dueñas-García Irma, Castañeda-Partida Laura, Sánchez-García Antonio, Contreras-Sousa Martha, Durán-Díaz Angel, Graf Ulrich
Laboratorio de Genética Toxicológica, FES Iztacala, Universidad Nacional Autónoma de México, 54090 Tlalnepantla, Estado de México, México.
Mutagenesis. 2004 May;19(3):187-93. doi: 10.1093/mutage/geh020.
Tamoxifen (TAM) is an anti-oestrogen used for treatment and prevention of human breast cancer, but it is also related to human endometrial and uterine cancer. The wing spot test in Drosophila melanogaster was employed to determine the genotoxic effects of TAM and 4-nitroquinoline-1-oxide (4-NQO), a carcinogen that produces adducts similar to TAM-DNA adducts detected in rodent liver and human liver microsomes. As Drosophila spp. have no oestrogen receptor, no effects can result in binding of TAM to a receptor. Chronic treatments with TAM citrate were performed with 3-day-old larvae of the standard (ST) and high bioactivation (HB) crosses of the wing spot test at concentrations of 0.66, 1.66 and 3.33 mM. In addition, the carcinogen 4-NQO was administered at 2.5 and 5.0 mM. Somatic spots on normal wings from marker-heterozygous flies and on serrate wings from balancer-heterozygous flies were scored to determine mutation and recombination events in somatic cells for each compound. The results showed genotoxic effects of TAM at 1.66 and 3.33 mM in the ST cross only and without a clear dose-response effect. This suggests a weak genotoxicity of this anti-oestrogen. The negative results obtained with TAM in the HB cross may indicate efficient detoxification of the compound by the increased xenobiotic metabolism present in this cross. As reported before, 4-NQO showed genotoxic effects in the ST cross with a clear dose-response effect. For the first time, we report enhanced effects of this compound in the HB cross. It is concluded that the genotoxicity of TAM in the Drosophila wing spot test is different from that of 4-NQO.
他莫昔芬（TAM）是一种用于治疗和预防人类乳腺癌的抗雌激素药物，但它也与人类子宫内膜癌和子宫癌有关。利用黑腹果蝇的翅斑试验来确定TAM和4-硝基喹啉-1-氧化物（4-NQO，一种致癌物，其产生的加合物类似于在啮齿动物肝脏和人类肝脏微粒体中检测到的TAM-DNA加合物）的遗传毒性作用。由于果蝇属没有雌激素受体，TAM与受体结合不会产生影响。用柠檬酸他莫昔芬对翅斑试验标准（ST）和高生物活化（HB）杂交品系的3日龄幼虫进行慢性处理，浓度分别为0.66、1.66和3.33 mM。此外，以2.5和5.0 mM的浓度施用致癌物4-NQO。对标记杂合子果蝇正常翅膀上的体细胞斑和平衡子杂合子果蝇锯齿状翅膀上的体细胞斑进行评分，以确定每种化合物在体细胞中的突变和重组事件。结果表明，仅在ST杂交品系中，1.66和3.33 mM的TAM具有遗传毒性作用，且没有明显的剂量反应效应。这表明这种抗雌激素具有较弱的遗传毒性。在HB杂交品系中TAM得到的阴性结果可能表明该杂交品系中存在的异生物质代谢增加对该化合物进行了有效解毒。如之前报道的那样，4-NQO在ST杂交品系中显示出遗传毒性作用，并具有明显的剂量反应效应。我们首次报道了该化合物在HB杂交品系中的增强效应。得出的结论是，TAM在果蝇翅斑试验中的遗传毒性与4-NQO不同。
