菌核净的抗雄激素作用及机制的研究  

The antiandrogenic effect of dimethachlon and its mechanism

作　　者：张国军[1] 郑一凡[1] 祝慧娟[1] 朱心强[1] 

机构地区：[1]浙江大学医学院毒理研究室

出　　处：《中华劳动卫生职业病杂志》2004年第1期15-18,共4页Chinese Journal of Industrial Hygiene and Occupational Diseases

摘　　要：目的　确定有机杂环类杀菌剂菌核净是否具有抗雄激素作用并探讨其可能的作用机制。方法　采用体内和体外相结合的方法 :体内实验采用经典的Hershberger试验 ,菌核净经口给药剂量为 50、10 0、2 0 0mg·kg- 1·d- 1;体外实验采用雄激素依赖基因转录活化试验 ,将人雄激素受体 (AR)表达质粒、AR 依赖荧光素酶报告质粒同时瞬时转染HepG2细胞 ,加入菌核净或已知抗雄激素 ,同时加或不加一定浓度的双氢睾酮以诱导荧光素酶基因的表达。结果　体内实验中 ,菌核净与已知抗雄激素一样能引起雄激素依赖组织重量明显降低 :染菌核净 2 0 0mg/kg组大鼠精囊腺、腹侧前列腺、背后侧前列腺、尿道球腺、提肛肌加球海绵体肌重量分别比溶剂对照组低 57.8%、44.8%、43 .9%、3 0 .1%、3 4 .1%。菌核净对雄激素依赖组织生长的抑制作用弱于氟他胺和腐霉利 ,但强于异菌脲。体外实验中 ,菌核净能抑制双氢睾酮依赖的AR活力 ,并呈现剂量 -反应关系 (r =-0 .952 3 ,P =0 .0 47)。菌核净的抑制作用较氟他胺弱 ,约为氟他胺的 1/10 0。结论　菌核净具有抗雄激素作用 ,是AR拮抗剂 ,其抗雄激素作用强度弱于氟他胺、腐霉利 。ObjectiveTo evaluate the antiandrogenic ef fect of heterocyclic fungicide dimethachlon and its mechanism. Method sA combination of in vivo and in vitro assays was selected. Hershberger assay was used to determine the antiandrogenic potential of dimethac hlon in vivo .Six-week-old castrated male SD rats were administrated once d aily for 7 days with testosterone propionate(TP,100 μg/d,sc) plus gavage doses of dimethachlon(50,100 or 200 mg·kg -1 ·d -1 ),or procymidone(150 or 3 00 mg·kg -1 ·d -1 ,positive control),or iprodione(100 mg·kg -1 ·d -1 ,positive control),or flutamide(50 mg·kg -1 ·d -1 ,positi ve control).Transcriptional activation assay in vitro was employed to determ ine the mechanism of antiandrogenic activity of dimethachlon.Human hepatoma live r cells HepG2 were transiently cotransfected with human androgen receptor(AR) ex pression plasmid and AR-dependent luciferase report plasmid.Transfected cells w ere exposed to various concentrations of dimethachlon or flutamide with or witho ut dihydrotestosterone to induce the expression of luciferase gene. ResultsIn Hershberge r assay,dimethachlon,as well as other known antiandrogens,caused decrease in wei ght of androgen dependent organs or tissues.In 200 mg/kg group,the weight of seminal vesicle,ventral prostate,dorsolateral prostate,Cowper's gland,and levat or 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 t heir antiandrogenic potencies was:flutamide>procymidone>dimethachlon>iprodione.I n transcriptional activation assay,dimethachlon could inhibit dihydrotestosteron e-dependent AR activity in transfected HepG2 cells in dose-effect relationship .The inhibiting potency of dimethachlon was about 1/100 of that of flutamide. ConclusionDimethachlon has antiandrogenic effect,and acts as an AR antagonist.Its antiandrogenic potency is lower than flutamide and procy midone,but higher than

关 键 词：菌核净 雄激素 作用机制 拮抗药 受体 

分 类 号：R96[医药卫生—药理学]