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研究生:葉麗冰
研究生(外文):Lai-Ping Yep
論文名稱:類固醇藥物對於同半胱胺酸代謝的影響
論文名稱(外文):Effects of glucocorticoids on homocysteine metabolism
指導教授:蔣恩沛
指導教授(外文):En-Pei Chiang
學位類別:碩士
校院名稱:國立中興大學
系所名稱:食品暨應用生物科技學系
學門:醫藥衛生學門
學類:營養學類
論文種類:學術論文
畢業學年度:96
語文別:英文
論文頁數:52
中文關鍵詞:類固醇藥物同半胱胺酸
外文關鍵詞:glucocorticoidhomocysteine
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固醇類藥物能有效的抑制發炎反應而廣泛的被運用來治療類風濕性關節炎、氣喘等疾病。前人研究發現固醇類藥物對於同半胱胺酸代謝的影響有不一致的結果。因此本研究探討在動物模式中,長期服用固醇類藥物對於單碳代謝的調控以及同半胱胺酸代謝的影響。
Prednisolone以腹腔注射四個禮拜。本研究利用甲硫胺酸負荷試驗來探討prednisolone對於同半胱胺酸代謝的影響。研究也測定腺苷甲硫胺酸、腺苷同半胱胺酸、同半胱胺酸、以及去氧核糖核酸甲基轉移酶的活性。同時本研究也測定了甲基循環中的基因表現,並利用穩定性同位素探討prednisolone對於同半胱胺酸代謝分流其再甲基化、轉甲基化和轉硫作用之影響。
結果發現 prednisolone 不影響甲硫胺酸負荷前和負荷後同半胱胺酸的濃度,但增加甲硫胺酸負荷後胱胺酸的濃度。Prednisolone增加了非肝組織的轉硫作用。我們發現prednisolone不影響腎臟中腺苷甲硫胺酸的合成、去氧核糖核酸甲基轉移酶活性。但是prednisolone卻特異性的抑制了肝臟中同半胱胺酸再甲基化、腺苷甲硫胺酸的合成以及去氧核糖核酸甲基轉移酶活性。肝臟中低濃度的腺苷甲硫胺酸與減少甲基化的程度相關。因此長期服用prednisolone可能會造成表觀遺傳調控的基因表現改變或增加基因不完整性的風險。至於長期服用prednisolone對於動物體內甲基化的影響則將在未來的研究中予以深入探討。
Background. Glucocorticoids such as prednisolone are potent and commonly used anti-inflammatory agents for the clinical treatment of human rheumatoid arthritis, asthma, and even in HIV-1-infected patients with severe pneumocystis pneumonia. In the literature, much remains to be clarified regarding the inconsistencies of the role of glucocorticoids on the metabolism of homocysteine. The present study was conducted to systematically investigate the effects of long-term prednisolone treatment on the regulation of one carbon metabolism and homocysteine kinetics in vivo.
Methods. After intraperitoneal injection of prednisolone to mice for 4 weeks, a methionine loading test was performed to investigate the impacts of prednisolone on homocysteine transsulfuration. AdoMet, adoHcy, homocysteine, and the impacts of prednisolone on DNA methyltransferase were determined. Genes participating the methylation cycle were examined. We also investigated the in vivo effects of prednisolone treatment on homocysteine metabolic fluxes in remethylation, transmethylation and transsulfuration using stable isotopic tracers.
Results. Prednisolone treatment increased post-methionine load cysteine without affecting fasting or post- methionine load homocysteine. Prednisolone increased transsulfuration flux in extra-hepatic tissues but not in liver. On the other hand, prednisolone did not alter adoMet synthesis or DNA methyltransferase activity in kidney. Finally, prednisolone treatment specifically inhibited hepatic homocysteine remethylation, reduced hepatic adoMet syntheisis, and inhibited DNA methyltransferase activity.
Conclusion. In the present study we demonstrated the novel findings that prednisolone specifically inhibited hepatic adoMet synthesis and DNA methyltransferase. Reduced adoMet synthesis has been related to impaired capacity for methylation, and our study may also suggest that long-term prednisolone treatment may have epigenetic alterations in gene expression or may affect genomic integrity I humans. Future studies on the long-tern effects of prednisolone treatment on in vivo methylation reactions are warranted.
Abbreviations……………………………………………………………………. 2
Effects of glucocorticoids on homocysteine metabolism
Abstract……………………………………………………………………….. 3
Introduction…………………………………………………………………... 5
Materials and methods……………………………………………………… 9
Result………………………………………………………………………….. 15
Discussion……………………………………………………………………... 21
Figure and Table……………………………………………………………… 31
References…………………………………………………………………….. 44
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