口服D型甲硫胺酸對順鉑處理之慢性毒性模式誘發腎毒性及厭食/惡病質之效果評估

順鉑（Cisplatin）為廣泛使用於治療實體腫瘤之化學治療藥劑，因Cisplatin會產生嚴重的副作用，如腎毒性、厭食/惡病質等，導致臨床上的使用限制，根據文獻指出，大多數的含硫化合物具有對抗Cisplatin誘導細胞毒性的功能。D型甲硫胺酸（D-methionine，L型甲硫胺酸之右旋異構物）為一種含硫胺基酸，且可作為強效的抗氧化物。本研究擬探討口服D-methionine對Cisplatin誘導腎毒性及厭食/惡病質之影響，我們將Wistar品系之雄性大鼠以每組8隻，隨機分成三組，本研究設計為慢性毒性模式，實驗過程為期3周，實驗大鼠每周腹腔注射Cisplatin (5 mg/kg body wt)（此為Cisplatin組），另外在處理Cisplatin的前3天起，開始每日給予管餵D-methionine (300 mg/kg body wt)（此為Cisplatin合併D-methionine組），而對照組則不處理以上藥物（此為Control組）。實驗結果發現，D-methionine可以顯著的回復Cisplatin處理之大鼠的體重減輕，增加大鼠的每日攝食量，也可以改善Cisplatin誘導的胃排空速度減慢，接著我們進一步的探討，發現Cisplatin會抑制肝臟中脂質新生作用和向上調控肌肉萎縮相關基因表現（如FOXO1, MAFbx），而D-methionine可以顯著的減緩此變化，改善骨骼肌和脂肪組織流失的情形；在腎毒性的部分，我們發現D-methionine可以趨緩Cisplatin處理之大鼠的血液尿素氮（BUN）的上升和腎臟的發炎反應，腎臟病理組織切片的觀察發現， D-methionin可以改善Cisplatin誘導的嚴重腎損傷，除此之外，我們發現大鼠經Cisplatin處理後，腎組織會出現脂質過氧化產物-丙二醛（MDA）大量生成，且麩胱甘肽過氧化酶（GPx）之活性和麩胱甘肽（GSH）含量有下降的情形，口服D-methionin可以減緩上述的氧化壓力指標。本研究顯示，口服D-methionine可能具有保護Cisplatin誘導之腎毒性及厭食/惡病質的功效，因此D-methionine有潛力能改善使用Cisplatin帶來的副作用，並可能成為未來病患在接受化學治療時的營養補充品。

Cisplatin is a widely used chemotherapeutic agent for the treatment of solid tumors. Its clinical use is limited due to severe side effects such as nephrotoxicity and anorexia/cachexia. Many sulfur containing compounds have been reported to protect against cisplatin-induced cytotoxicity. D-methionine, dextro-isomer of L-methionine, is a sulfur containing amino acid and can act as potent antioxidants. In this study, we investigate the effects of oral D-methionine on cisplatin-induced nephrotoxicity and anorexia/cachexia. Male Wistar rats were divided into three treatment groups of eight rats each. The study schedule was designed in a chronic experiment model, which rats received cisplatin (5 mg/kg body wt) intraperitoneal injection once a week for 3 weeks (cisplatin group). The animals were pre-treated with D-methionine (300 mg/kg body wt) daily by gavage for 3 days before cisplatin administration (cisplatin combined D-methionine group). The control group remains untreated. The results suggested that D-methionine significantly reverse the reduction of body weight, increase daily food intake, and enhance gastric emptying after cisplatin treatment. We also observed that cisplatin suppresses lipogensis in liver tissues and up-regulates the muscle atrophy markers gene expression (such as FOXO1, MAFbx). The loss of skeletal muscles mass and adipose tissue are regained by D-methionine administration, which might be partly through retard liver lipogensis and modulated muscle atrophy-related mRNA expression. On the other hand, we found the treatment with D-methionine mitigates the cisplatin nephrotoxicity which caused the increasing level of blood urea nitrogen (BUN) and the renal inflammation. Histopathological examination revealed that D-methionine improved severe renal damage induced by cisplatin. Moreover, the renal malondialdehyde (MDA) production in cisplatin-administrated rats was markedly increased and the activity of glutathione peroxidase (GPx) and glutathione (GSH) content were also declined. D-methionine significantly attenuated the above oxidative stress markers caused by cisplatin. Our result indicated that oral D-methionine could protect against cisplatin-induced nephrotoxicity and anorexia/cachexia. Therefore, D-methionine has the potential to alleviate the side effects of cisplatin and serve as novel nutritional supplements when patients are undergoing their chemotherapy.