甲硫胺酸 (methionine, Met) 代謝中間產物同半胱胺酸 (homocysteine, Hcy) 可透過甲基化，以維生素B12及葉酸為輔酶轉變為甲硫胺酸，或透過轉硫化以維生素B6為輔酶轉變為cystathionine。若代謝過程中之酵素或維生素B6、B12與葉酸缺乏即會造成高同半胱胺酸血症 (hyperhomocysteinemia, HHcy)。研究指出，給予高同半胱胺酸血症患者維生素B6、B12或葉酸則能降低其血漿同半胱胺酸濃度。許多實驗亦證實同半胱胺酸會誘增反應性氧物質 (reactive oxygen species, ROS) 之生成而造成氧化壓力，而氧化壓力尤其會破壞富含多元不飽和脂肪酸 (polyunsaturated fatty acids, PUFA) 的細胞膜，進而破壞細胞功能。而睪丸之細胞膜因富含多元不飽和脂肪酸，易受氧化壓力影響而與男性不孕疾病有關。前人研究亦顯示，高同半胱胺酸血症與許多腎臟相關疾病，包括尿毒症、腎衰竭與末期腎臟疾病有關。此外，研究亦指出餵食台農二號山藥後能降低血漿同半胱胺酸濃度。因此，本研究主要目的在探討給予甲硫胺酸、甲硫胺酸同時混合維生素B6、B12、葉酸或台農二號山藥後對大鼠睪丸與腎臟之影響。

　　給予Wistar 雄鼠甲硫胺酸、甲硫胺酸同時混合維生素B6、B12、葉酸或台農二號山藥，八週後測其睪丸與腎臟之氧化壓力指標 (Hcy、ROS、MDA) 與抗氧化指標 (CAT、SOD、GSH、GSSG、GPx、GR)，以及觀察組織結構。結果顯示，在氧化壓力指標上，甲硫胺酸顯著誘增血漿 Hcy 與 MDA，以及睪丸與腎臟之 ROS 與 MDA (p<0.01)；在給予維生素B6、B12、葉酸或台農二號山藥後顯著降低血漿 Hcy 與 MDA (p<0.01)；葉酸或台農二號山藥顯著降低睪丸 ROS 含量；葉酸顯著降低但山藥顯著增加腎臟 ROS 含量 (p<0.01)；維生素B12或葉酸顯著降低睪丸 MDA 濃度 (p<0.01)，維生素B6、B12或台農二號山藥顯著降低腎臟之MDA 濃度 (p<0.01)。觀察組織結構顯示，甲硫胺酸組曲細精管間 Spermatogenic 細胞比控制組稀疏，其精子生成量亦較控制組少，以及腎絲球之間質細胞過度增生、腎絲球間質腫脹與毛細化。在給予維生素B6、葉酸或台農二號山藥後能回復睪丸與腎臟之氧化傷害，但維生素B12只能回復睪丸卻無法回復腎臟之氧化傷害。

　　在抗氧化指標方面，甲硫胺酸顯著降低睪丸 SOD，腎臟 CAT 以及 GR，但顯著增加睪丸 CAT 與腎臟 GPx (p<0.01)。給予葉酸顯著增加睪丸與腎臟 CAT；維生素B12或葉酸顯著降低睪丸 GSH 與 GSSG，維生素B6或B12顯著降低
但台農二號山藥顯著增加腎臟 GSH，維生素B12或葉酸顯著降低但台農二號山藥顯著增加腎臟 GSSG (p<0.01)；維生素B12或葉酸顯著增加睪丸 GPx (p<0.01)，維生素B12顯著增加但葉酸顯著降低腎臟 GPx (p<0.01)；維生素B12或台農二號山藥顯著增加但葉酸顯著降低睪丸 GR (p<0.01)，維生素B6、B12、葉酸或台農二號山藥顯著降低腎臟GR (p<0.01)。

　　本研究結果發現， (1) 長期腹腔注射甲硫胺酸能穩定地誘增血漿同半胱胺酸之濃度，(2) 腹腔注射甲硫胺酸的確能誘增睪丸與腎臟之氧化壓力，(3) 維生素B6、B12、葉酸與台農二號山藥能分別降低血漿、睪丸與腎臟之氧化傷害，(4) 維生素B6、B12、葉酸與台農二號山藥能藉由降低抗氧化性指標之活性，表示已降低甲硫胺酸所誘增之氧化壓力，以及藉由增加抗氧化性指標之活性，表示其增加清除自由基之能力。因此，本研究結論，維生素B6、B12、葉酸與台農二號山藥確實可保護睪丸與腎臟免於甲硫胺酸與同半胱胺酸所誘發之氧化傷害。

　　Homocysteine (Hcy) is a sulfur-containing amino acid whose metabolism stands at the intersection of two pathways including remethylation to methionine (Met) which requires folate and vitamin B12, and transsulfuration to cystathionine which requires vitamin B6.Hyperhomocysteinemia (HHcy) arises from impairment of Hcy metabolism resulting from the deficiency of vitamin B6, B12 or folic acid and has been shown to induce oxidative stress. Studies showed that HHcy treated with vitamin B6、B12 or folic acid could effectively lower plasma Hcy levels. Recently, Hcy has been found to production of reactive oxygen species (ROS) leading to oxidative stress that induce was reported to damage the polyunsaturated fatty acids (PUFA) on the cell membrane, causing the impairment of cellular functions. Studies also showed that
　
　　HHcy was associated with renal diseases including stages of renal dialysis, renal failure and end-stage renal disease. Testicular membranes are rich in PUFA and highly susceptible to oxidative stress which is implicated in male infertility. In our previous study, we found that Dioscorea alata L. cv. Tainong 2 could decrease plasma Hcy concentration. The present work was undertaken to investigate the oxidative, antioxidative indicators and histology of testis and kidney in HHcy rats supplemented with Met, Met plus vitamin B6, B12, folic acid or Dioscorea alata L. cv. Tainong 2 simultaneously.
HHcy was induced by i.p injection of Met at dose 300 mg/KgBW daily for 8 weeks. Oxidative (Hcy, ROS, MDA) and antioxidative (CAT, SOD, GSH, GSSG, GPx and GR) indicators, and histology of HHcy rats were investigated. Results of oxidative indicators showed that Met group significantly increased Hcy and MDA levels in plasma (p<0.01), ROS and MDA levels in the testis and kidney compare to the control (p<0.01). Vitamin B6, B12, folic acid or Dioscorea alata L. cv. Tainong 2 significantly decreased Hcy and MDA levels in plasma (p<0.01), folic acid or Dioscorea alata L. cv. Tainong 2 significantly decreased testicular ROS levels (p<0.01), folic acid significantly decreased but Dioscorea alata L. cv. Tainong 2 significantly increased renal ROS levels (p<0.01), vitamin B12 or folic acid
significantly decreased testicular MDA levels (p<0.01), vitamin B6, B12 or Dioscorea alata L. cv. Tainong 2 significantly decreased renal MDA levels (p<0.01). Histological examinations showed that Met group had rare of spermatogenic cells and spermatozoa in the seminiferous tube of testis, over-proliferation of mesangial cell, glomerular extracellular matrix was increased in the kidney. The glomerular mesangium was expanded with hypercellularity and capillary collapse in the kidney of the Met group. Vitamin B6, folic acid or Dioscorea alata L. cv. Tainong 2 reversed the development of spermatogenic cells and spermatogenesis in the testis, glomerular structure in the kidney but except vitamin B12 in the kidney.

　　The antioxidative indicators of our data showed that Met group significantly decreased testicular SOD and increased CAT (p<0.01), significantly decreased renal CAT, GR and increased GPx compare to the control group (p<0.01). Folic acid significantly increased testicular and renal CAT (p<0.01), vitamin B12 or folic acid significantly decreased testicular GSH and GSSG levels (p<0.01), vitamin B6 or B12 significantly decreased but Dioscorea alata L. cv. Tainong 2 significantly increased renal GSH levels (p<0.01), vitamin B12 or folic acid significantly decreased but Dioscorea alata L. cv. Tainong 2 significantly increased renal GSSG levels (p<0.01). Vitamin B12 or folic acid significantly increased testicular GPx (p<0.01), vitamin B12 significantly increased but folic acid significantly decreased renal GPx (p<0.01). Vitamin B12 or Dioscorea alata L. cv. Tainong 2 significantly increased but folic acid could significantly decreased testicular GR (p<0.01)；vitamin B6, B12, folic acid or Dioscorea alata L. cv. Tainong 2 significantly decreased renal GR (p<0.01).

　　In summary, (I) methionine injection intraperitoneally (i.p.) could stably induce high Hcy concentrations for a period of time, (II) intraperitoneally injection of Met could induce oxidative stress in the testis and kidney, (III) vitamin B6, B12, folic acid or Dioscorea alata L. cv. Tainong 2 could significantly decrease oxidative damage induced by Met in the plasma, testis and kidney, (IV) vitamin B6, B12, folic acid or Dioscorea alata L. cv. Tainong 2 did not furthur induce antioxidative activity, which might be due to the use up of the antioxidative enzymes for scavenging the ROS induced by the Met. In conclusion, vitamin B6, B12, folic acid or Dioscorea alata L. cv. Tainong 2 could protect testis and kidney against the oxidative stress of HHcy induced by Met in this study.

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