- 學位論文
貝芬替對大鼠細胞色素P450之影響
Effect of Carbendazim on Cytochrome P450s in Rats
摘要
貝芬替是廣泛且具有系統性的殺菌劑，用來控制植物發霉、腐爛和枯萎。貝芬替和相關的benzimidazoles在大鼠中顯示出具有生殖毒性和內分泌干擾作用。細胞色素P450在代謝上是屬於第一級的酵素系統，對藥物、致癌物、類固醇類的賀爾蒙和環境汙染物的代謝功能。本研究的主要目的是探討貝芬替在大鼠肝、腎、肺和睪丸細胞色素P450及抗氧化酵素的調控。雄性大鼠以腹腔注射貝芬替，處理劑量分別為10、50、100 mg/kg，1天1次進行4天，造成睪丸的精子數目呈劑量效應的下降關係。在肝臟微粒體中，貝芬替處理增加P450 content、NADPH-cytochrome P450 reductase、7-ethoxyresorufin O-deethylase (EROD)、methoxyresorufin O-demethylase (MROD)、pentoxyresorufin O-dealkylase和7-ethoxycoumarin O-deethylase (ECOD)酵素活性。在腎臟微粒體中，貝芬替增加P450 content、EROD和ECOD酵素活性。在肺臟微粒體中，貝芬替處理增加EROD酵素活性。在睪丸微粒體中，貝芬替增加NADPH-cytochrome P450 reductase 酵素活性。貝芬替增加肝臟細胞液中的glutathione S-transferase (GST)、catalase酵素活性以及在睪丸細胞液中的GST和superoxide dismutase酵素活性。此殺菌劑會降低腎臟中的glutathione content和睪丸組織中的脂質過氧化。口服400 mg/kg 貝芬替7天會增加肝臟微粒體中MROD酵素活性。在西方點墨法和RT-PCR分析中，在肝臟組織中CYP1A1/2和CYP2B的蛋白量和mRNA皆增加；在腎臟和肺臟中則是CYP1A1的蛋白量和mRNA增加。在目前的研究中發現，貝芬替是大鼠中CYP1A1/2和CYP2B的誘導物。在酵素活性上經貝芬替顯著誘導的細胞色素P450需要再進一步的探討。
並列摘要
Carbendazim (methyl-2-benzimidazole carbamate) is a broad spectrum and systemic fungicide for the control of molds, rots, and blight. Carbendazim and related benzimidazoles show marked reproductive toxicity and endocrine-disrupting activity in rats. Cytochrome P450 (CYP) is the primary enzyme system in metabolism and is responsible for the metabolism of drugs, carcinogens, steroid hormones, and environmental pollutants. CYP genes are markedly responsive to the stimulatory and inhibitory effects of xenobiotics and provide a powerful tool to investigate gene-environment interaction. The major objective of the present study was to investigate the ability of carbendazim to modulate CYP-dependent monooxygenases and antioxidant enzymes in rat liver, kidney, lung, and testis. Treatment of male rats with 10, 50, and 100 mg/kg carbendazim intraperitoneally once daily for 4 days decreased testis spermatid density dose-dependently. In liver microsomes, the carbendazim treatment increased P450 content, NADPH-cytochrome c reductase, 7-ethoxyresorufin O-deethylase (EROD), methoxyresorufin O-demethylase (MROD), pentoxyrsorufin O-dealkylase, and 7-ethoxycoumarin O-deethylase (ECOD) activities. In kidney microsomes, carbendazim increased P450 content and EROD and ECOD activities. In lung microsomes, the treated increased EROD activity. In testis microsomes, the treatment increased NADPH-cytochrome c reductase activity. Carbendazim increased glutathione S-transferase (GST) and catalase activities in liver cytosol and GST and superoxide dismutase activities in testis cytosol. The fungicide decreased glutathione content in the kidneys and lipid peroxidation in the testes. Oral administration of 400 mg/kg carbendazim for 7 days increased MROD activity in liver microsomes. The results of immunoblot and RT-PCR analyses showed that carbendazim induced CYP1A1/2 and CYP2B proteins and mRNA in the liver and CYP1A1 protein and mRNA in kidneys and lungs. These present findings show that carbendazim is an inducer of CYP1A1/2 and CYP2B in rats. The significance of carbendazim induction of CYP in metabolic activation warrants further investigations.
參考文獻
延伸閱讀
- 楊智廸（2020）。農藥得克利對雄鼠細胞色素P450、氧化壓力及內分泌干擾作用之研究〔博士論文，國立臺灣大學〕。華藝線上圖書館。https://doi.org/10.6342/NTU202002510
- Su, C. C., Kiyokawa, M., Liao, J., Kao, C. W., Hsieh, M. T., Chung, J. G., & Hung, C. F. (2000). Lomustine對大白鼠神經膠質瘤之體外培養細胞中乙醯轉移酶活性的影響. 放射治療與腫瘤學, 7(1), 9-14. https://doi.org/10.6316/TRO/200007(1)9
- 林侑璇（2007）。一、七種人類細胞色素P450 3A4受質抑制土震素代謝反應之研究;二、以RAF值探討細胞色素P450 3A於大鼠及人體肝臟微粒體中土震素代謝的角色〔碩士論文，國立臺灣大學〕。華藝線上圖書館。https://doi.org/10.6342/NTU.2007.01284
- 楊婕舲（2011）。染布青萃出物對大鼠Clone 9 肝細胞pi屬麩胱甘肽轉移酶表現之影響〔碩士論文，中山醫學大學〕。華藝線上圖書館。https://doi.org/10.6834/CSMU.2011.00160
- Gallo, L. L., Tian, Y., Orfalian, Z., & Fiskum, G. (1992). Amelioration of popolysaccharide-induced sepsis in rats by free and esterified carnitine. Mediators of Inflammation, 1993(), s51-s56. https://doi.org/10.1155/S0962935193000766