[滴滴涕的抗雄激素作用及其机制]

[The antiandrogenic effect of dimethachlon and its mechanism].

作者信息

Zhang Guo-jun, Zheng Yi-fan, Zhu Hui-juan, Zhu Xin-qiang

机构信息

Toxicology Department, Zhejiang University, Hangzhou 310031, China.

出版信息

Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2004 Feb;22(1):15-8.

PMID:15033008

Abstract

OBJECTIVE

To evaluate the antiandrogenic effect of heterocyclic fungicide dimethachlon and its mechanism.

METHODS

A combination of in vivo and in vitro assays was selected. Hershberger assay was used to determine the antiandrogenic potential of dimethachlon in vivo. Six-week-old castrated male SD rats were administrated once daily for 7 days with testosterone propionate (TP, 100 micro g/d, sc) plus gavage doses of dimethachlon (50, 100 or 200 mg x kg(-1) x d(-1)), or procymidone (150 or 300 mg x kg(-1) x d(-1), positive control), or iprodione (100 mg x kg(-1) x d(-1), positive control), or flutamide (50 mg x kg(-1) x d(-1), positive control). Transcriptional activation assay in vitro was employed to determine the mechanism of antiandrogenic activity of dimethachlon. Human hepatoma liver cells HepG2 were transiently cotransfected with human androgen receptor (AR) expression plasmid and AR-dependent luciferase report plasmid. Transfected cells were exposed to various concentrations of dimethachlon or flutamide with or without dihydrotestosterone to induce the expression of luciferase gene.

RESULTS

In Hershberger assay, dimethachlon, as well as other known antiandrogens, caused decrease in weight of androgen dependent organs or tissues. In 200 mg/kg group, the weight of seminal vesicle, ventral prostate, dorsolateral prostate, Cowper's gland, and levator ani plus bulbocavernosus muscles decreased by 57.8%, 44.8%, 43.9%, 30.1%, and 34.1% respectively, but did not decrease in the vehicle control group. The order of their antiandrogenic potencies was: flutamide > procymidone > dimethachlon > iprodione. In transcriptional activation assay, dimethachlon could inhibit dihydrotestosterone-dependent AR activity in transfected HepG2 cells in dose-effect relationship. The inhibiting potency of dimethachlon was about 1/100 of that of flutamide.

CONCLUSION

Dimethachlon has antiandrogenic effect, and acts as an AR antagonist. Its antiandrogenic potency is lower than flutamide and procymidone, but higher than iprodione.

摘要

目的

评估杂环类杀菌剂抑霉唑的抗雄激素作用及其机制。

方法

选择体内和体外试验相结合的方法。采用赫什伯格试验来测定抑霉唑在体内的抗雄激素潜力。对6周龄去势雄性SD大鼠每日一次连续7天给予丙酸睾酮（TP，100μg/d，皮下注射）加灌胃不同剂量的抑霉唑（50、100或200mg·kg⁻¹·d⁻¹），或腐霉利（150或300mg·kg⁻¹·d⁻¹，阳性对照），或异菌脲（100mg·kg⁻¹·d⁻¹，阳性对照），或氟他胺（50mg·kg⁻¹·d⁻¹，阳性对照）。采用体外转录激活试验来确定抑霉唑抗雄激素活性的机制。将人雄激素受体（AR）表达质粒和AR依赖性荧光素酶报告质粒瞬时共转染人肝癌细胞HepG2。将转染后的细胞暴露于不同浓度的抑霉唑或氟他胺，同时添加或不添加二氢睾酮以诱导荧光素酶基因的表达。

结果

在赫什伯格试验中，抑霉唑以及其他已知的抗雄激素药物均导致雄激素依赖器官或组织重量减轻。在200mg/kg组中，精囊、腹侧前列腺、背外侧前列腺、考珀氏腺以及提肛肌加球海绵体肌的重量分别下降了57.8%、44.8%、43.9%、30.1%和34.1%，而溶剂对照组则无下降。它们的抗雄激素效力顺序为：氟他胺＞腐霉利＞抑霉唑＞异菌脲。在转录激活试验中，抑霉唑能够在转染的HepG2细胞中呈剂量效应关系抑制二氢睾酮依赖性AR活性。抑霉唑的抑制效力约为氟他胺的1/100。