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首页> 外文期刊>Archives of Toxicology >Mechanistic study on liver tumor promoting effects of flutamide in rats
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Mechanistic study on liver tumor promoting effects of flutamide in rats

机译：氟他胺促进大鼠肝肿瘤的机制研究

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Flutamide (FLU), a nonsteroidal anti-androgen, is used for the treatment of prostate cancer but is also a cytochrome P450 (CYP) 1A inducer. Some CYP1A inducers are known to exert hepatocellular tumor-promoting activities in rodents, and reactive oxygen species (ROS) produced by CYP1A1 induction via a metabolism of FLU is probably involved in the liver tumor promotion. In the present study, to clarify the possible liver tumor promoting effect of FLU, a two-stage liver carcinogenesis assay was performed using male F344 rats. Rats received an intraperitoneal (ip) injection of 200 mg/kg body weight of N-diethylnitrosamine (DEN) and fed a diet containing 0, 0.1 or 0.2% FLU for 6 weeks. After 2 weeks of DEN treatment, all rats were subjected to two-thirds partial hepatectomy. Animals were killed 8 weeks after ip injection of DEN. Immunohistochemically, the number and area of glutathione S-transferase placental form (GST-P)-positive foci significantly increased in the liver of rats given 0.2% FLU as compared with the control. Ki-67-positive cell ratio also increased in rats given FLU at both concentrations. ROS generation in the microsomal fraction and production of thiobarbituric acid-reactive substance [TBARS] and 8-hydroxy-2′-deoxyguanosine (8-OHdG) content in the liver did not increase in any of the FLU-treated groups. The results of microarray and real-time RT-PCR revealed that phase 1 drug-metabolizing enzymes such as CYP1A1, Ugt1a61 and Nqo1 and phase II drug-metabolizing enzymes such as Yc2, Akr1b7, Akr1b8, Akr1b10, Aldh1a1, Gpx2 and Me1 were up-regulated in rats treated with FLU. In addition, the MAPK pathway family-related genes such as Prkcα, Mek1, Rafb, Myc, Mek2, Raf1 and Egfr were also up-regulated in FLU-treated groups. The results of the present study indicate that FLU is a CYP1A inducer but does not cause any production of microsomal ROS in the liver and suggest that microsomal ROS is not involved in the liver tumor promoting effect of FLU.
机译：非甾体类抗雄激素Flutamide（FLU）用于治疗前列腺癌，但它也是细胞色素P450（CYP）1A诱导剂。已知某些CYP1A诱导剂在啮齿动物中发挥肝细胞促肿瘤活性，而CYP1A1诱导通过FLU代谢产生的活性氧（ROS）可能参与了肝肿瘤的促进。在本研究中，为了阐明FLU可能对肝肿瘤的促进作用，使用雄性F344大鼠进行了两阶段肝癌变试验。大鼠接受腹膜内（ip）注射200 mg / kg体重的N-二乙基亚硝胺（DEN），并喂食含0、0.1或0.2％FLU的饮食6周。 DEN治疗2周后，对所有大鼠进行三分之二的肝部分切除术。腹膜内注射DEN后8周将动物处死。免疫组织化学分析，给予0.2％FLU的大鼠肝脏中谷胱甘肽S-转移酶胎盘形式（GST-P）阳性灶的数量和面积与对照组相比明显增加。在两种浓度下均给予FLU的大鼠中，Ki-67阳性细胞比例也增加。在任何FLU治疗组中，肝脏的微粒体级分中的ROS生成以及硫代巴比妥酸反应性物质[TBARS]和8-羟基-2'-脱氧鸟苷（8-OHdG）的含量均未增加。芯片和实时RT-PCR结果表明，CYP1A1，Ugt1a61和Nqo1等第一阶段药物代谢酶和Yc2，Akr1b7，Akr1b8，Akr1b10，Aldh1a1，Gpx2和Me1等II期药物代谢酶均升高在用FLU治疗的大鼠中调节。另外，在FLU治疗组中，与MAPK途径家族相关的基因如Prkcα，Mek1，Rafb，Myc，Mek2，Raf1和Egfr也被上调。本研究的结果表明，FLU是CYP1A的诱导剂，但在肝脏中不引起微粒体ROS的产生，并且表明微粒体ROS不参与FLU对肝脏肿瘤的促进作用。

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