Yang Jr-Di, Liu Shing-Hwa, Liao Mei-Hsiu, Chen Ruei-Ming, Liu Pei-Yu, Ueng Tzuu-Huei
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC.
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC.
Environ Toxicol. 2018 Jun 19. doi: 10.1002/tox.22575.
The major objective of the present study was to determine the ability of a triazole fungicide tebuconazole to induce cytochrome P450-dependent monooxygenases, oxidative stress, and endocrine-disrupting activity using male rats treated with tebuconazole at 10, 25, and 50 mg/kg p.o. once daily for 28 days. In liver, tebuconazole dose-dependently increased microsomal contents of cytochrome P450 and cytochrome b and the activities of NADPH-cytochrome P450 reductase, 7-ethoxyresorufin O-deethylase, methoxyresorufin O-demethylase, pentoxyresorufin O-dealkylase, 7-ethoxycoumarin O-deethylase, aniline hydroxylase, and erythromycin N-demethylase. In kidney, tebuconazole increased 7-ethoxycoumarin O-deethylase activity without affecting other monooxygenase activities. In marked contrast to liver and kidney, tebuconazole decreased testicular 7-ethoxyresorufin O-deethylase, methoxyresorufin O-demethylase, 7-ethoxycoumarin O-deethylase, aniline hydroxylase, and erythromycin N-demethylase activities. The results of immunoblot analysis of liver microsomes of controls and tebuconazole-treated rats revealed that tebuconazole induced CYP1A1/2, CYP2B1/2, CYP2E1, and CYP3A proteins in liver. Additions of tebuconazole to liver microsomes inhibited microsomal 7-ethoxycoumarin O-deethylase activity in vitro (IC = 1.50-1.69 µM). Treatment of rats with tebuconazole decreased glutathione content and increased glutathione S-transferase, superoxide dismutase, catalase, and glutathione peroxidase activities in liver; increased superoxide dismutase activities in kidney and testis; but decreased glutathione S-transferase activity in testis. Treatments with tebuconazole decreased serum testosterone concentration and cauda epididymal sperm count. The present study demonstrates that tebuconazole induces a multiplicity of CYPs and oxidative stress in liver; inhibits testicular P450 and glutathione S-transferase activities; and produces anti-androgenic effects in male rats.
本研究的主要目的是，通过对雄性大鼠口服戊唑醇，剂量分别为10、25和50mg/kg，每日一次，持续28天，来确定三唑类杀菌剂戊唑醇诱导细胞色素P450依赖性单加氧酶、氧化应激和内分泌干扰活性的能力。在肝脏中，戊唑醇剂量依赖性地增加了细胞色素P450和细胞色素b的微粒体含量，以及NADPH-细胞色素P450还原酶、7-乙氧基异吩恶唑酮O-脱乙基酶、甲氧基异吩恶唑酮O-脱甲基酶、戊氧基异吩恶唑酮O-脱烷基酶、7-乙氧基香豆素O-脱乙基酶、苯胺羟化酶和红霉素N-脱甲基酶的活性。在肾脏中，戊唑醇增加了7-乙氧基香豆素O-脱乙基酶的活性，但不影响其他单加氧酶的活性。与肝脏和肾脏形成鲜明对比的是，戊唑醇降低了睾丸中7-乙氧基异吩恶唑酮O-脱乙基酶、甲氧基异吩恶唑酮O-脱甲基酶、7-乙氧基香豆素O-脱乙基酶、苯胺羟化酶和红霉素N-脱甲基酶的活性。对对照组和戊唑醇处理组大鼠肝脏微粒体进行免疫印迹分析的结果显示，戊唑醇在肝脏中诱导了CYP1A1/2、CYP2B1/2、CYP2E1和CYP3A蛋白。在体外，向肝脏微粒体中添加戊唑醇会抑制微粒体7-乙氧基香豆素O-脱乙基酶的活性（IC = 1.50 - 1.69µM）。用戊唑醇处理大鼠会降低肝脏中的谷胱甘肽含量，并增加谷胱甘肽S-转移酶、超氧化物歧化酶、过氧化氢酶和谷胱甘肽过氧化物酶的活性；增加肾脏和睾丸中的超氧化物歧化酶活性；但降低睾丸中的谷胱甘肽S-转移酶活性。用戊唑醇处理会降低血清睾酮浓度和附睾尾精子计数。本研究表明，戊唑醇在肝脏中诱导多种细胞色素P450和氧化应激；抑制睾丸中的P450和谷胱甘肽S-转移酶活性；并在雄性大鼠中产生抗雄激素作用。
