Cook J C, Mullin L S, Frame S R, Biegel L B
Haskell Laboratory for Toxicology and Industrial Medicine, E. I. du Pont de Nemours & Company, Newark, Delaware 19714.
Toxicol Appl Pharmacol. 1993 Apr;119(2):195-204. doi: 10.1006/taap.1993.1060.
In a previously conducted 2-year study, a concentration-dependent increase in Leydig cell adenomas was observed in Crl:CD BR(CD) rats fed diets containing the herbicide linuron. Linuron has been shown to be negative in a battery of six tests for genotoxicity; therefore, a nongenotoxic mechanism of tumorgenesis was investigated. Linuron is structurally related to the nonsteroidal antiandrogen, flutamide. Flutamide has also been shown to produce Leydig cell tumors within 1 year, presumably due to sustained hypersecretion of luteinizing hormone (LH) which occurs following disruption of the hypothalamic-pituitary-testicular (HPT) axis. To investigate whether linuron possesses antiandrogenic activity, sexually immature and mature CD rats were administered either 200 mg/kg linuron or 10 mg/kg flutamide (positive control) for 2 weeks. Accessory sex organs were weighed and serum hormone levels were measured to assess androgen status and alterations in the HPT axis. Serum from a multigeneration reproduction study with linuron was also analyzed for serum hormone levels. In addition, competitive receptor binding studies were conducted to evaluate the ability of linuron to bind to the androgen receptor. Linuron decreased accessory sex organ weights in sexually immature and mature linuron-treated rats. Increased serum estradiol and LH levels were observed in sexually mature linuron-treated rats. Serum estradiol and LH levels were also elevated in P1 and F1 male rats from the multigeneration reproduction study. These accessory sex organ and hormonal changes are consistent with those seen with the antiandrogen flutamide, the only exception being serum testosterone, which was elevated following exposure to flutamide but not to linuron. The inability of linuron to increase testosterone levels may reflect the lower potency of linuron as an antiandrogen compared with that of flutamide, which is a potent antiandrogen. Additionally, linuron competed with [3H]testosterone for binding to the androgen receptor. The IC50 data for competition to the androgen receptor suggest that linuron is approximately 3.5 times less potent than flutamide. These data are consistent with the effects seen with flutamide and demonstrate that linuron is a less potent antiandrogen than flutamide. Collectively, these data support the hypothesis that linuron produces Leydig cell tumors via an antiandrogenic mechanism where sustained hypersecretion of LH appears to be responsible for the development of Leydig cell hyperplasia and adenomas.
在之前一项为期两年的研究中，给Crl:CD BR(CD)大鼠喂食含除草剂利谷隆的日粮，观察到其睾丸间质细胞瘤呈浓度依赖性增加。利谷隆在一系列六项遗传毒性试验中呈阴性；因此，对其非遗传毒性致癌机制进行了研究。利谷隆在结构上与非甾体抗雄激素药物氟他胺相关。氟他胺也已被证明在1年内会产生睾丸间质细胞瘤，可能是由于下丘脑-垂体-睾丸（HPT）轴受到破坏后促黄体生成素（LH）持续过度分泌所致。为了研究利谷隆是否具有抗雄激素活性，对性未成熟和成熟的CD大鼠分别给予200mg/kg利谷隆或10mg/kg氟他胺（阳性对照），持续2周。称量附属生殖器官重量并测量血清激素水平，以评估雄激素状态和HPT轴的变化。还分析了利谷隆多代繁殖研究中的血清激素水平。此外，进行了竞争性受体结合研究，以评估利谷隆与雄激素受体结合的能力。利谷隆降低了性未成熟和成熟的利谷隆处理大鼠的附属生殖器官重量。在性成熟的利谷隆处理大鼠中观察到血清雌二醇和LH水平升高。在多代繁殖研究的P1和F1雄性大鼠中，血清雌二醇和LH水平也升高。这些附属生殖器官和激素变化与抗雄激素药物氟他胺的情况一致，唯一的例外是血清睾酮，氟他胺暴露后血清睾酮升高，而利谷隆暴露后未升高。利谷隆不能提高睾酮水平可能反映出与强效抗雄激素药物氟他胺相比，利谷隆作为抗雄激素的效力较低。此外，利谷隆与[3H]睾酮竞争结合雄激素受体。与雄激素受体竞争的IC50数据表明，利谷隆的效力比氟他胺低约3.5倍。这些数据与氟他胺的作用一致，表明利谷隆作为抗雄激素的效力低于氟他胺。总体而言，这些数据支持了以下假设：利谷隆通过抗雄激素机制产生睾丸间质细胞瘤，其中LH的持续过度分泌似乎是睾丸间质细胞增生和腺瘤发生的原因。
