臺灣博碩士論文加值系統

近年發現 2,5,7,8-tetramethyl-2-(2’-carboxyethyl)-6-hydroxychroman (alpha-CEHC) 為維生素 E 側鏈被切短後的水溶性代謝產物。目前推測其側鏈截短之代謝途徑牽涉到 omega-hydroxylation 及支鏈 beta-oxidation。由於催化 omega-hydroxylation 之酵素 cytochrome P450 4A1 (CYP4A1) 及過氧化體 beta-oxidation 的酵素 acyl-CoA oxidase 1 (ACO1) 均為受 peroxisome proliferator-activated receptor alpha (PPARalpha) 調控之下游基因。為探討 PPARalpha 對維生素 E 代謝生成 alpha-CEHC 之影響效應，本研究以大鼠之動物模式，投予 PPARalpha 活化劑 clofibrate 及 perfluorodecanoic acid (PFDA) 誘發 PPARalpha 標的基因表現，觀察活化 PPARalpha 傳訊途徑對鼠尿中維生素 E 代謝產物 alpha-CEHC 排出量之影響。
alpha-CEHC 於體內會與 glucuronic acid 或 sulfate 等結合，形成alpha-CEHC conjugate，隨尿液排出體外。文獻分析樣品 alpha-CEHC之方法，多用 beta-glucuronidase 酵素水解 alpha-CEHC conjugates，再以 high performance liquid chromatography with electrochemical detector (HPLC-ECD) 定量之。然而，本實驗發現鼠尿經 HCl 強酸處理後，HPLC-ECD 所測得之 alpha-CEHC 含量會明顯竄升，以 beta-glucuronidase 酵素處理者則否。為確認鼠尿 alpha-CEHC conjugate之結構，我們將鼠尿進行純化分離，經化學結構鑑定確認此HCl releasable alpha-CEHC conjugate為 6-O-sulfated alpha-CEHC (alpha-CEHC sulfate)。另外，我們亦重建酸水解萃取分析尿液 conjugated alpha-CEHC 之方法：將含抗壞血酸之樣品，以 6 N HCl 於 60度C 反應 1 小時進行酸加熱水解，之後以乙醚萃取，續以 HPLC-ECD 進行 alpha-CEHC 定量分析。在熱酸水解過程中，以抗壞血酸作為抗氧化劑可以有效地保護 alpha-CEHC不被破壞。此分析方法的優點為快速、靈敏及回收率佳。
動物實驗共分三部分進行。實驗一採雙因子變因設計，分別給予大鼠餵食含 50 mg/kg all-rac-alpha-tocopheryl acetate (alpha-TA) (L 組)、50 mg/kg alpha-TA + 0.5% clofibrate ( LC 組)、500 mg/kg alpha-TA (H 組) 或 500 mg/kg alpha-TA + 0.5% clofibrate ( HC 組) 之試驗飼料為期一週，其間並收集尿液。結果顯示 clofibrate 處理會造成大鼠肝臟及血清 alpha-tocopherol (alpha-TOH) 含量明顯下降及肝臟中 PPARalpha 下游基因 ACO1、CYP4A1 及 D-bifunctional protein (D-BF) 之酵素活性、蛋白質或 m-RNA 表現量顯著增加。尿液 alpha-CEHC 排出量方面，LC 組老鼠之每日 alpha-CEHC 排出量顯著高於 L 組老鼠 (p<0.05)，HC 組卻稍低於 H 組。若將 alpha-CEHC 排出量以佔每日飲食維生素 E 攝入量的比例來表示，可以發現LC 組老鼠之 alpha-CEHC 排出量顯著高於 L 組 (p<0.05)，HC 組老鼠之 alpha-CEHC 排出量略高於 H 組，但組間無統計差異。
延續實驗一之結果，實驗二改以管餵方式提供正常劑量之維生素 E (5 mg alpha-TA/kg B.W./day)，觀察給予含 0 (C 組)、0.1 % (0.1P 組)、0.25% (0.25P 組)、0.5% (0.5P 組) 或 1 % (1P 組) 之 clofibrate 試驗飼料一週，對維生素E代謝之影響。結果顯示，clofibrate 處理會造成 PPARalpha 標的基因 ACO1、CYP4A1及參與支鏈脂肪酸代謝之 ACO2 及 D-BF 等之酵素活性、蛋白質或 mRNA 表現量顯著增加，且具劑量效應之趨勢。尿液中每日 alpha-CEHC 排出量亦隨 clofibrate 處理劑量增加而上升。且 ACO1、CYP4A1、ACO2 及 D-BF之表現與尿液alpha-CEHC 排出量呈顯著之正相關性 (r=0.30-0.46, p<0.05)。
實驗三則在正常維生素 E 劑量 (50 mg alpha-TA/kg diet) 試驗飼料下，每日以腹腔方式給予 0、0.5、1、2.5、5 或 10 mg/kg B.W. 之 PFDA，誘發 PPARalpha 傳訊途徑，觀察不同類型之 PPARalpha 活化劑對維生素E代謝之影響。結果顯示，PFDA 同樣會造成 PPARalpha 下游基因 ACO1、CYP4A1等之酵素活性、蛋白質或 m-RNA 表現量顯著增加，且具劑量效應。尿液中每日 alpha-CEHC 排出量亦隨 PFDA 處理劑量增加而上升。PPARalpha 下游基因 ACO1、CYP4A1之表現與尿液alpha-CEHC 排出量呈顯著之正相關 (r=0.40-0.56, p<0.05)。至於，目前文獻中提及可能參與維生素 E 代謝之相關蛋白質，如 CYP3A、CYP4F等，於本實驗中其 mRNA或蛋白質表現量與尿液 alpha-CEHC 排出量無關聯性，甚至呈負相關。
因此，本研究之結果初步證實利用 PPARalpha 活化劑 clofibrate 及 PFDA 誘發 PPARalpha 標的基因的表現，會促進體內維生素 E代 謝，增加尿液中 alpha-CEHC 的排出量。活化 PPARalpha 傳訊途徑可能會影響體內維生素 E 的代謝。

2,5,7,8-tetramethyl-2-(2’-carboxyethyl)-6-hydroxychroman (alpha-CEHC), the metabolite of alpha-tocopherol (alpha-TOH) with a shortened side chain but an intact hydroxychroman structure, has been identified in the urine. Pathway of the metabolism involves omega-hydroxylation of phytyl side chain and the following beta-oxidation. omega-Hydroxylation is known to be catalyzed by cytochrome P450 enzymes (CYPs), of which CYP3A and CYP4F is the most likely candidates. The enzymes which are responsible for the omega-oxidation (CYP4A1) and peroxisomal beta-oxdiation (acyl-CoA oxidase 1, ACO1) of fatty acid are transcriptionally regulated by peroxisome proliferator activated receptor alpha (PPARalpha). In order to investigate effects of PPARalpha activation on the vitamin E metabolism, Wistar rats were treated with PPARalpha activators - clofibrate and perfluorodecanoic acid (PFDA) and urinary alpha-CEHC was monitored in this study.
alpha-CEHC was known to be conjugated with glucuronic acid or sulfate. Various CEHCs in biological specimen were mostly measured by high performance liquid chromatography with electrochemical detector (HPLC-ECD) preceded by beta-glucuronidase hydrolysis. In an attempt to analyze alpha-CEHC in rat urine accordingly, it observed that enzyme hydrolysis was relatively inefficient in releasing alpha-CEHC compared to high concentrations of HCl. The HCl releasable alpha-CEHC conjugate was therefore isolated and chemically identified as 6-O-sulfated alpha-CEHC (alpha-CEHC sulfate). Using the synthetic alpha-CEHC sulfate standard, it was found that sulfatase could not hydrolyze to a significant extent. On the other hand, pretreatment with HCl at 60。C in the presence of ascorbate, followed by a one-step ether extraction not only hydrolyzed the sulfate conjugate completely but also extracted alpha-CEHC with high recovery. The inclusion of ascorbate minimized the conversion of alpha-CEHC to alpha-tocopheronolactone in the HCl pretreatment. A complete procedure for the quantitative analysis of alpha-CEHC including HCl hydrolysis, ether extraction and reverse phase isocratic HPLC-ECD was thus established.
A total of three rat experiments were conducted to examine the effects of PPARalpha activators on urinary alpha-CEHC excretion. In Experiment 1, rats were fed diets containing 50 mg/kg all-rac-alpha-tocopheryl acetate (alpha-TA) (L), 50 mg/kg alpha-TA + 0.5% clofibrate ( LC ), 500 mg/kg alpha-TA (H) or 500 mg/kg alpha-TA + 0.5%clofibrate (HC) for 1 week, and the urine was collected for alpha-CEHC analysis. PPARalpha target genes including CYP4A1, ACO1 and D-BF is induced significantly by clofibrate revealed by the expression of enzyme activity, protein or mRNA. Clofibrate treatment resulted in a significant decrease of the alpha-TOH content in serum and liver. The urinary alpha-CEHC content of LC group is significantly higher than that of the L group (p<0.05). The ratio of urinary alpha-CEHC to dietary vitamin E intake of the LC group is also significantly higher than the L group. However, no significant difference between H and HC group was found.
In Experiment 2, rats were fed vitamin E devoid AIN-76 modified diets containing 0 (C), 0.1 (0.1CF), 0.25 (0.25CF), 0.5 (0.5CF), 1 (1CF) % clofibrate and were i.p. injected with 5 mg alpha-TA/kg B.W. daily for 1 week. Expressions of PPARalpha target genes, namely, CYP4A1, ACO1, ACO2 and D-BF that participated in the metabolism of fatty acid were all increased significantly and does-dependently by the clofibrate treatment as revealed by the of enzyme activity, protein or mRNA expression. The urinary alpha-CEHC excretion of all clofibrate treated groups were also increased does-dependently (p<0.05). Again, there were significantly positive correlations between the urinary alpha-CEHC and the expression of CYP450, CYP4A1 and ACO1 (r=0.40-0.56, p<0.05).
In Experiment 3, another PPARalpha activator PFDA was used. All of the 6 groups of rats were fed the AIN-76 modified diet containing 50 mg/kg alpha-TA and respectively tube-fed vehicle (C) or 0.5 (0.5P), 1(1P), 2.5 (2.5P), 5 (5P) or 10 (10P) mg/kg body weight of PFDA daily for 1 week. PPARalpha target genes - CYP4A1 and ACO1 expression in the liver also increased significantly and does-dependently by PFDA as revealed by enzyme activity, protein or mRNA expression (p<0.05). The urinary alpha-CEHC content of all PFDA treated groups also increased does-dependently (p<0.05). Positive correlations between the urinary alpha-CEHC and the expression of CYP4A1 and ACO1 were again observed (r=0.42-0.50, p<0.05). However, CYP3A and CYP4F which has been considered to catalyze vitamin E catabolism to alpha-CEHC showed no correlation with urinary alpha-CEHC in this study (p>0.05).
In conclusion, this study demonstrates that PPARalpha activation is associated with an increased urinary alpha-CEHC excretion. The activation of PPARalpha signal pathway may enhance the vitamin E catabolism through up-regulation of some of its target genes (ex. CYP4A1 and ACO1).

目 錄
中文摘要i
英文摘要iii
縮寫對照表v
第一章 緒言1
第一節 研究動機與目的1
第二節 文獻回顧2
一、維生素 E 簡介2
二、維生素 E 的吸收、運轉與分佈4
三、維生素 E的生理功能 7
四、維生素 E 的抗氧化代謝產物 8
五、維生素 E的非抗氧化代謝產物 CEHCs 11
六、過氧化體增殖劑活化受器 (PPAR) 29
七、Xenobiotics 代謝 33
第三節 實驗假說與研究架構 40
一、實驗假說 40
二、研究架構 40
第二章 鼠尿 alpha-CEHC sulfate 純化鑑定與 conjugated alpha-CEHC分析方法之重建 41
第一節 前言 41
第二節 材料方法 43
一、化學藥品及試劑配製 43
二、鼠尿及人尿樣品 44
三、Conjugated alpha-CEHC 之不同水解方式及其萃取步驟 45
四、HPLC 分析 48
五、分離、純化與鑑定 51
六、統計分析 54
第三節 結果 55
一、HCl 酸水解對鼠尿 alpha-CEHC 含量分析結果之影響 55
二、鼠尿經 HCl水解後於 HPLC-ECD 分析中所得 alpha-CEHC 波峰之成分確認 55
三、鼠尿中 HCl-releasable alpha-CEHC conjugate 之分離、純化與鑑定58
四、以酸水解分析尿液 alpha-CEHC 條件之再確認 65
五、比較人尿與鼠尿 alpha-CEHC conjugates 之異同 80
第四節 討論與結論 82
一、鼠尿 alpha-CEHC conjugates 之型式 82
二、Sulfatase 酵素無法有效地水解 alpha-CEHC sulfate 83
三、Ascorbic acid 可以有效抑制 alpha-CEHC 生成 alpha-tocopheronolactone83
四、Free alpha-CEHC 與 total alpha-CEHC 的關聯性 84
五、維生素 E 的代謝與 sulfation 84
六、結論 85
第三章 降血脂藥物 clofibrate 對維生素 E代謝生成 alpha-CEHC 之影86
第一節 前言 86
第二節 材料與方法 88
一、實驗大綱 88
二、試驗飼料的配製 90
三、動物飼養 90
四、尿液收集 93
五、動物犧牲及組織樣品收集 93
六、血液脂質分析 93
七、肝臟脂質分析 95
八、血清及肝臟之 alpha-tocopherol 含量分析 96
九、尿液 alpha-CEHC 含量分析 98
十、尿液 creatinine 含量分析 98
十一、肝臟 CYP450 總含量分析 99
十二、肝臟過氧化體 ACO1 活性分析 101
十三、以西方轉漬法分析肝臟 ACO1 及 CYP4A1 蛋白質含量 105
十四、以北方轉漬法分析肝臟 PPARalpha 下游基因之 mRNA 表現量 109
十五、統計分析 115
第三節 結果 116
一、生長狀況 116
二、血清及肝臟脂質含量 119
三、血清及肝臟 alpha-tocopherol 含量 120
四、尿液 alpha-CEHC 排出量 124
五、飲食維生素 E 攝入量與尿液 alpha-CEHC 排出量之關係 125
六、肝臟微粒體 CYP450 總含量 130
七、肝臟過氧化體 ACO1活性 130
八、肝臟 CYP4A1 及 ACO1 蛋白質表現量 133
九、肝臟 PPARalpha 傳訊途徑相關之基因 mRNA 表現量 133
十、尿液 alpha-CEHC 排出量與維生素 E 攝入量、血清及肝臟 alpha-tocopherol 含量之相關性分析 138
十一、 尿液 alpha-CEHC 排出量與clofibrate 劑量、肝臟 CYP450含量及PPARalpha 下游基因ACO 、CYP4A1 等之活性、蛋白質或 mRNA表現量之相關性分析 138
第四節 討論與結論 143
一、Clofibrate 對動物生長狀況之影響效應 143
二、Clofibrate 對 PPARalpha 標的基因及參與脂肪酸代謝相關基因之影響143
三、飲食維生素 E 含量對體內維生素 E 含量及尿液 alpha-CEHC 排出量之影響 144
四、活化 PPARalpha 傳訊途徑對體內維生素 E 含量及尿液 alpha-CEHC 排出量之影響 145
五、PPARalpha 傳訊途徑與維生素 E 代謝生成 alpha-CEHC 之關聯性 147
六、維生素 E 對 PPARalpha 及其標的基因之影響 147
七、結論 149
第四章 環境污染物 PFDA 對維生素 E 代謝生成 alpha-CEHC 之影150
第一節 前言 150
第二節 材料與方法 152
一、實驗大綱 152
二、試驗飼料的配製 153
三、動物飼養 153
四、尿液收集 154
五、動物犧牲及樣品收集 154
六、血液脂質分析 154
七、肝臟脂質分析 154
八、血漿、肝臟及脂肪組織之 alpha-tocopherol 含量分析 154
九、尿液、血清及肝臟總 alpha-CEHC 含量分析 155
十、肝臟 CYP450 總含量分析 155
十一、肝臟過氧化體 ACO1 活性分析 156
十二、以西方轉漬法分析 ACO1, CYP4A1 及 CYP3A1/2 蛋白質含量156
十三、以 Real-time PCR分析 PPARalpha 及 PXR下游基因等之 mRNA 表現量156
十四、統計分析158
第三節 結果 159
一、生長狀況 159
二、血清及肝臟脂質含量 162
四、尿液 alpha-CEHC 排出量 166
五、血清及肝臟 alpha-CEHC 含量 166
六、肝臟微粒體 CYP450 總含量 173
七、肝臟微粒體各CYP 蛋白質表現量 173
八、肝臟過氧化體 ACO1 酵素活性及蛋白質表現量 174
九、肝臟中與 PPAR alpha 及脂肪酸代謝相關基因之 mRNA 表現量 178
十、肝臟中與維生素 E 代謝相關基因之 mRNA 表現量 179
十一、 尿液 alpha-CEHC 排出量與肝臟 CYPP450含量、PPARalpha 或脂肪酸代謝相關基因等之活性、蛋白質或 mRNA表現量之相關性分析181
十二、 尿液 alpha-CEHC 排出量與已知可能參與維生素 E 相關代謝蛋白質之相關性分析 181
第四節 討論與結論 184
一、PFDA 對動物生長狀況之影響效應 184
二、PFDA 對體內脂質代謝之影響 184
三、PFDA 對 PPARalpha 標的基因及參與脂肪酸代謝相關基因之影響185
四、PFDA 對體內維生素 E 及 alpha-CEHC 含量之影響 185
五、PFDA 對參與維生素 E 相關代謝蛋白質之影響 186
六、PPARalpha 傳訊途徑與維生素 E 代謝生成 alpha-CEHC 之關聯性 189
七、結論 190
第五章 綜合討論與總結論 191
第六章 參考文獻 196
附錄206

圖目錄
圖 1-1 維生素 E 的化學結構2
圖 1-2 維生素 E 與自由基反應之代謝途徑及其產物9
圖 1-3 Simon’s 代謝物10
圖 1-4 維生素 E 之可能代謝途徑 14
圖 1-5 PPAR/RXR 之活化機制30
圖 1-6 粒線體與過氧化體之脂肪酸 beta-oxidation 33
圖 1-7 UDPGT 催化之 glucuronidation 反應36
圖 1-8 SULT 催化之 sulfation 反應37
圖 1-9 維生素 E 與 xenobiotics 代謝之相互作用39
圖 2-1 鼠尿經酵素或酸水解處理後之 HPLC-ECD 層析圖56
圖 2-2 以製備式 RP-18 HPLC 純化鼠尿經酸處理之 alpha-CEHC 目標產物及其成分鑑定 57
圖 2-3 鼠尿 HCl-releasable alpha-CEHC conjugates 之純化流程與 HPLC 層析圖61
圖 2-4 鼠尿 conjugated alpha-CEHC (6-O-sulfated alpha-CEHC) 之成分鑑定 63
圖 2-5 HCl 添加劑量 (A) 與 pH 值 (B) 對大鼠尿液之 alpha-CEHC 與 alpha-tocopheronolactone 測定值之影響70
圖 2-6 HCl添加劑量 (A) 與 pH 值 (B) 對 alpha-CEHC sulfate 標準品溶液之 alpha-CEHC 與 alpha-tocopheronolactone測定值之影響 72
圖 2-7 以 HPLC-UV 定量加酸處理 alpha-CEHC sulfate 標準品溶液樣品之 alpha-tocopheronolactone 層析圖譜74
圖2-8 HCl添加劑量 (A) 與 pH 值 (B) 對 alpha-CEHC 標準品溶液之 alpha-CEHC 與 alpha-tocopheronolactone測定值之影響75
圖 2-9 比較不同水解方式對鼠尿生成 alpha-CEHC 之影響78
圖 3-1 肝臟過氧化體 ACO1 酵素活性測定之原理103
圖3-2 維生素 E 與降血脂藥物 clofibrate 對大鼠肝臟過氧化體 ACO1 及微粒體 CYP4A1蛋白質表現量之影響135
圖 3-3 維生素 E 與降血脂藥物 clofibrate 對大鼠對大鼠肝臟CYP4A1, ACO1 及
D-BF mRNA 表現量之影響136
圖3-4不同劑量 clofibrate 處理後對大鼠肝臟 CYP4A1, ACO1/2, L-BF 及 D-BF mRNA 表現量之影響137
圖 3-5 不同劑量 clofibrate 處理後對大鼠尿液 alpha-CEHC 排出量與clofibrate 處理劑量、肝臟 CYP450 總量ACO1 活性之相關性分析141
圖 3-6 不同劑量 clofibrate 處理七天後對大鼠尿液 alpha-CEHC 排出量與肝臟 CYP4A1, ACO1/2, L-BF 及 D-BF mRNA表現量之相關性分析142
圖4-1 PFDA 之化學結構151
圖4-2 不同劑量 PFDA 處理對大鼠每日尿液 alpha-CEHC 排出量之影響170
圖4-3 各組大鼠從適應期至處理期之尿液 alpha-CEHC 變化量171
圖4-4 PFDA 處理對大鼠血清、肝臟 alpha-CEHC 含量及第七天尿液 alpha-CEHC 排出量之相關性分析172
圖4-5 不同劑量 PFDA 處理對大鼠肝臟 ACO1, CYP4A1, CYP3A1/2蛋白質表現量之影響177
圖4-6 不同劑量 PFDA 處理對大鼠肝臟 PPARalpha, CYP4A1, ACO1/2/3, PXR, CYP3A, CYP4F 及SULT mRNA 表現量之影響180
圖4-7 PFDA 處理對大鼠尿液 alpha-CEHC 排出量與肝臟 CYP450 總量、ACO 活性及 ACO1, CYP4A1, CYP3A1/2 蛋白質表現量之相關性分析183
圖5-1 維生素 E 代謝生成 alpha-CEHC 之可能路徑195
表 1-1 探討維生素 E 代謝途徑之相關文獻15
表 1-2 CEHCs 分析偵測方法之文獻統整.21
表 1-3 CYPs 的誘發受到不同核受器的調節35
表 2-1 alpha-CEHC、alpha-CEHC sulfate 標準品與鼠尿中 alpha-CEHC sulfate 之13C與 1H NMR 光譜之比較64
表 2-2 HCl添加劑量對大鼠尿液之 alpha-CEHC 與 alpha-tocopheronolactone測定值之影響71
表 2-3 HCl添加劑量對 alpha-CEHC sulfate 標準品溶液之 alpha-CEHC 與 alpha-tocopheronolactone測定值之影響73
表 2-4 HCl添加劑量對 alpha-CEHC標準品溶液之 alpha-CEHC 與 alpha-tocopheronolactone測定值之影響76
表 2-5 不同水解方式對 alpha-CEHC sulfate溶液生成 alpha-CEHC 與
alpha-tocopheronolactone 之影響77
表 2-6 鼠尿與 alpha-CEHC sulfate標準品溶液不同酸水解方式之 alpha-CEHC 回收率試驗79
表2-7 以不同水解方式處理鼠尿或人尿之 alpha-CEHC 定量結果81
表3-1 實驗一之試驗飼料組成91
表3-2 實驗二之試驗飼料組成92
表3-3 維生素 E 與降血脂藥物 clofibrate 對大鼠體重增加、攝食量及飼料利用效率之影響117
表3-4 維生素 E 與降血脂藥物 clofibrate 對大鼠各組織相對重量之影響118
表3-5維生素 E 與降血脂藥物 clofibrate 對大鼠血清及肝臟中三酸甘油酯及膽固醇含量之影響122
表3-6 維生素 E 與降血脂藥物 clofibrate 對大鼠血清及肝臟中 alpha-tocopherol 含量影響123
表3-7 維生素 E 與降血脂藥物 clofibrate 對大鼠飲水量、排尿量及尿液肌酸酐含量之影響127
表3-8 維生素 E 與降血脂藥物 clofibrate 對大鼠尿液中 alpha-CEHC含量之影響128
表3-9 維生素 E 與降血脂藥物 clofibrate 對大鼠維生素 E 攝入量對尿液中 alpha-CEHC排出量之影響 129
表3-10 維生素 E 與降血脂藥物 clofibrate 對大鼠肝臟微粒體中CYP450含量之影響131
表3-11 維生素 E 與降血脂藥物 clofibrate 對大鼠肝臟過氧化體 ACO1 活性之影響132
表3-12 維生素 E 與降血脂藥物 clofibrate 對大鼠尿液中 alpha-CEHC排出量與其維生素 E 攝入量、肝臟及血清 alpha-tocopherol 含量之相關性分析139
表3-13 維生素 E 與降血脂藥物 clofibrate 對大鼠尿液中 alpha-CEHC排出量與肝臟 CYP450 總量、ACO1 活性及 CYP4A1 蛋白質含量之相關性分析140
表4-1試驗飼料組成 153
表4-2 不同劑量 PFDA 處理對大鼠體重增加、攝食量及飼料利用效率之影響160
表4-3 不同劑量 PFDA 處理對大鼠各組織相對重量之影響 161
表4-4 不同劑量 PFDA 處理對大鼠血清及肝臟中三酸甘油酯及膽固醇含量之影響163
表4-5 不同劑量 PFDA 處理對大鼠血清、肝臟及脂肪組織 alpha-tocopherol 含量之影響165
表4-6 不同劑量 PFDA 處理對大鼠維生素 E 攝取量、喝水量、排尿量及尿液 alpha-CEHC含量之影響之影響 168
表4-7 不同劑量PFDA 處理對大鼠血清及肝臟 alpha-CEHC含量之影響 169
表4-8 不同劑量 PFDA 處理對大鼠肝臟微粒體中CYP450含量之影響175
表4-9 不同劑量PFDA 處理對大鼠肝臟過氧化體 ACO1 活性之影響 176
表4-10 PFDA 處理對大鼠尿液中 alpha-CEHC排出量與肝臟PPARalpha, ACO1/2/3, CYP4A1, PXR, CYP3A, CYP4F及SULT mRNA含量之相關性分析182
表5-1 Clofibrate 及 PFDA 對維生素 E 代謝生成 alpha-CEHC 之影響總整理 192

李宜靜 (2004) 尿中 alpha-CEHC 對飲食維生素 E 攝取量之反映評估。台灣大學微生物與生化學研究所碩士論文。
何偲慈 (2009) 大鼠尿液及血漿中維生素 E 代謝物 alpha-CEHC 對維生素 E 營養狀況之反映性。台灣大學微生物與生化學研究所碩士論文。
林甫容 (2002) 以鼠肝癌細胞株 H4IIEC3 初探幾種 PPARalpha 化物對維生素 E 代謝產物 alpha-CEHC 生成之影響。台灣大學農業化學研究所碩士論文。
陳永如 (2007) 數種植物雌激素食材萃物對 PPAR、脂肪細胞生成及雌激素活性特質鑑定。台灣大學微生物與生化學研究所碩士論文。
黃玟綺 (2008) 氧化炸油對大鼠維生素 E 代謝相關蛋白質與基因表現之影響。嘉南藥理科技大學營養與保健科技研究所碩士論文。
劉珍芳 (1993) 炸油餵食對老鼠體內維生素 E 代謝之影響。台灣大學農業化學研究所博士論文。
鄭啟承 (2002) 飲食維生素 E 及 clofibric acid 對大鼠尿中維生素 E 代謝物 alpha-CEHC 排出之影響初探。台灣大學農業化學研究所碩士論文。
鄭瑋宜 (2007) 山藥具雌激性活性成份之單離與鑑定研究。台灣大學微生物與生化學研究所博士論文。
羅聲晴 (2006) 以維生素 E 代謝物 alpha-CEHC 於血漿中含量為評估維生素 E 營養狀況之可行性初探。台灣大學微生物與生化學研究所碩士論文。
(1977) Report of the American Institute of Nurtition ad hoc Committee on Standards for Nutritional Studies. J Nutr 107, 1340-1348.
Abe C, Uchida T, Ohta M, Ichikawa T, Yamashita K & Ikeda S (2007) Cytochrome P450-Dependent Metabolism of Vitamin E Isoforms is a Critical Determinant of Their Tissue Concentrations in Rats. Lipids 42, 637-645.
Azzi A, Gysin R, Kempna P, Munteanu A, Villacorta L, Visarius T & Zingg JM (2004) Regulation of gene expression by alpha-tocopherol. Biol Chem 385, 585-591.
Betancor-Fernandez A, Sies H, Stahl W & Polidori MC (2002) In vitro antioxidant activity of 2,5,7,8-tetramethyl-2-(2''-carboxyethyl)-6-hydroxychroman (alpha-CEHC), a vitamin E metabolite. Free Radic Res 36, 915-921.
Bieri JG (1972) Kinetics of tissue -tocopherol depletion and repletion. Ann N Y Acad Sci 203, 181-191.
Birringer M, Drogan D & Brigelius-Flohe R (2001) Tocopherols are metabolized in HepG2 cells by side chain omega-oxidation and consecutive beta-oxidation. Free Radic Biol Med 31, 226-232.
Birringer M, Pfluger P, Kluth D, Landes N & Brigelius-Flohe R (2002) Identities and differences in the metabolism of tocotrienols and tocopherols in HepG2 cells. J Nutr 132, 3113-3118.
Blatt DH, Leonard SW & Traber MG (2001) Vitamin E kinetics and the function of tocopherol regulatory proteins. Nutrition 17, 799-805.
Blouin A, Bolender RP & Weibel ER (1977) Distribution of organelles and membranes between hepatocytes and nonhepatocytes in the rat liver parenchyma. A stereological study. J Cell Biol 72, 441-455.
Brigelius-Flohe R (2007) Adverse effects of vitamin E by induction of drug metabolism. Genes Nutr 2, 249-256.
Brigelius-Flohe R, Kelly FJ, Salonen JT, Neuzil J, Zingg JM & Azzi A (2002) The European perspective on vitamin E: current knowledge and future research. Am J Clin Nutr 76, 703-716.
Brigelius-Flohe R & Traber MG (1999) Vitamin E: function and metabolism. Faseb J 13, 1145-1155.
Burchell B, Baird S & Coughtrie MW (1990) The role of xenobiotic glucuronidating enzymes in drug resistance of tumour tissues and cells. Princess Takamatsu Symp 21, 263-275.
Burton GW & Traber MG (1990) Vitamin E: antioxidant activity, biokinetics, and bioavailability. Annu Rev Nutr 10, 357-382.
Catignani GL (1975) An alpha-tocopherol binding protein in rat liver cytoplasm. Biochem Biophys Res Commun 67, 66-72.
Chan AC, Wagner M, Kennedy C, Chen E, Lanuville O, Mezl VA, Tran K & Choy PC (1998) Vitamin E up-regulates arachidonic acid release and phospholipase A2 in megakaryocytes. Mol Cell Biochem 189, 153-159.
Chapman E, Best MD, Hanson SR & Wong CH (2004) Sulfotransferases: structure, mechanism, biological activity, inhibition, and synthetic utility. Angew Chem Int Ed Engl 43, 3526-3548.
Cheeseman KH, Holley AE, Kelly FJ, Wasil M, Hughes L & Burton G (1995) Biokinetics in humans of RRR-alpha-tocopherol: the free phenol, acetate ester, and succinate ester forms of vitamin E. Free Radic Biol Med 19, 591-598.
Cheng WY, Kuo YH & Huang CJ (2007) Isolation and identification of novel estrogenic compounds in yam tuber (Dioscorea alata Cv. Tainung No. 2). J Agric Food Chem 55, 7350-7358.
Chiku S, Hamamura K & Nakamura T (1984) Novel urinary metabolite of d-delta-tocopherol in rats. J Lipid Res 25, 40-48.
Cho JY, Wook Kang D, Ma X, Ahn SH, Krausz KW, Luecke H, Idle JR & Gonzalez FJ (2009) Metabolomics reveals a novel vitamin E metabolite and attenuated vitamin E metabolism upon PXR activation. J Lipid Res 50, 924-937.
Chow CK, Draper HH, Csallany AS & Chiu M (1967) The metabolism of C(14)-alpha-tocopheryl quinone and C(14)-alpha-tocopheryl hydroquinone. Lipids 2, 390-396.
Cominacini L, Garbin U, Pasini AF, Davoli A, Campagnola M, Contessi GB,
Pastorino AM & Lo Cascio V (1997) Antioxidants inhibit the expression of intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1 induced by oxidized LDL on human umbilical vein endothelial cells. Free Radic Biol Med 22, 117-127.
Corton JC, Anderson SP & Stauber A (2000) Central role of peroxisome proliferator-activated receptors in the actions of peroxisome proliferators. Annu Rev Pharmacol Toxicol 40, 491-518.
Desrumaux C, Deckert V, Athias A, Masson D, Lizard G, Palleau V, Gambert P & Lagrost L (1999) Plasma phospholipid transfer protein prevents vascular endothelium dysfunction by delivering alpha-tocopherol to endothelial cells. FASEB J 13, 883-892.
Desvergne B & Wahli W (1999) Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev 20, 649-688.
Dimitrov NV, Meyer C, Gilliland D, Ruppenthal M, Chenoweth W & Malone W (1991) Plasma tocopherol concentrations in response to supplemental vitamin E. Am J Clin Nutr 53, 723-729.
Eaton S, Bartlett K & Pourfarzam M (1996) Mammalian mitochondrial beta-oxidation. Biochem J 320 ( Pt 2), 345-357.
Eisengart A, Milhorat AT, Simon EJ & Sundheim L (1956) The metabolism of vitamin E. II. Purification and characterization of urinary metabolites of alpha-tocopherol. J Biol Chem 221, 807-817.
Escher P & Wahli W (2000) Peroxisome proliferator-activated receptors: insight into multiple cellular functions. Mutat Res 448, 121-138.
Folch J, Lees M & Sloane Stanley GH (1957) A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 226, 497-509.
Freiser H & Jiang Q (2009a) Gamma-tocotrienol and gamma-tocopherol are primarily metabolized to conjugated 2-(beta-carboxyethyl)-6-hydroxy-2,7,8-trimethylchroman and sulfated long-chain carboxychromanols in rats. J Nutr 139, 884-889.
Freiser H & Jiang Q (2009b) Optimization of the enzymatic hydrolysis and analysis of plasma conjugated gamma-CEHC and sulfated long-chain carboxychromanols, metabolites of vitamin E. Anal Biochem 388, 260-265.
Galli F, Stabile AM, Betti M, Conte C, Pistilli A, Rende M, Floridi A & Azzi A (2004) The effect of alpha- and gamma-tocopherol and their carboxyethyl hydroxychroman metabolites on prostate cancer cell proliferation. Arch Biochem Biophys 423, 97-102.
Glauert HP, Beaty MM, Clark TD, Greenwell WS, Tatum V, Chen LC, Borges T, Clark TL, Srinivasan SR & Chow CK (1990) Effect of dietary vitamin E on
the development of altered hepatic foci and hepatic tumors induced by the peroxisome proliferator ciprofibrate. J Cancer Res Clin Oncol 116, 351-356.
Goeptar AR, Scheerens H & Vermeulen NP (1995) Oxygen and xenobiotic reductase activities of cytochrome P450. Crit Rev Toxicol 25, 25-65.
Gonzalez FJ (2002) The peroxisome proliferator-activated receptor alpha (PPARalpha): role in hepatocarcinogenesis. Mol Cell Endocrinol 193, 71-79.
Gross CS, Milhorat AT & Simon EJ (1956) The metabolism of vitamin E. I. The absorption and excretion of d-alpha-tocopheryl-5-methyl-C14-succinate. J Biol Chem 221, 797-805.
Hardwick JP, Song BJ, Huberman E & Gonzalez FJ (1987) Isolation, complementary DNA sequence, and regulation of rat hepatic lauric acid omega-hydroxylase (cytochrome P-450LA omega). Identification of a new cytochrome P-450 gene family. J Biol Chem 262, 801-810.
Hashimoto T (1999) Peroxisomal beta-oxidation enzymes. Neurochem Res 24, 551-563.
Hattori A, Fukushima T & Imai K (2000) Occurrence and determination of a natriuretic hormone, 2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxy chroman, in rat plasma, urine, and bile. Anal Biochem 281, 209-215.
Hayashi T, Kanetoshi A, Nakamura M, Tamura M & Shirahama H (1992) Reduction of alpha-tocopherolquinone to alpha-tocopherolhydroquinone in rat hepatocytes. Biochem Pharmacol 44, 489-493.
Homolya L, Varadi A & Sarkadi B (2003) Multidrug resistance-associated proteins: Export pumps for conjugates with glutathione, glucuronate or sulfate. Biofactors 17, 103-114.
Hosomi A, Arita M, Sato Y, Kiyose C, Ueda T, Igarashi O, Arai H & Inoue K (1997) Affinity for alpha-tocopherol transfer protein as a determinant of the biological activities of vitamin E analogs. FEBS Lett 409, 105-108.
Huang WC, Kang ZC, Li YJ & Shaw HM (2009) Effects of Oxidized Frying Oil on Proteins Related to alpha-Tocopherol. J. Clin Biochem Nutr (accepted).
Ikeda S, Tohyama T & Yamashita K (2002) Dietary sesame seed and its lignans inhibit 2,7,8-trimethyl- 2(2''-carboxyethyl)-6-hydroxychroman excretion into urine of rats fed gamma-tocopherol. J Nutr 132, 961-966.
Issemann I & Green S (1990) Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 347, 645-650.
Jiang Q & Ames BN (2003) Gamma-tocopherol, but not alpha-tocopherol, decreases proinflammatory eicosanoids and inflammation damage in rats. Faseb J 17, 816-822.
Jiang Q, Elson-Schwab I, Courtemanche C & Ames BN (2000) gamma-tocopherol
and its major metabolite, in contrast to alpha-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells. Proc Natl Acad Sci U S A 97, 11494-11499.
Jiang Q, Freiser H, Wood KV & Yin X (2007) Identification and quantitation of novel vitamin E metabolites, sulfated long-chain carboxychromanols, in human A549 cells and in rats. J. Lipid Res. 48, 1221-1230.
Johnson EF, Palmer CN, Griffin KJ & Hsu MH (1996) Role of the peroxisome proliferator-activated receptor in cytochrome P450 4A gene regulation. FASEB J 10, 1241-1248.
Kalsotra A, Anakk S, Boehme CL & Strobel HW (2002) Sexual dimorphism and tissue specificity in the expression of CYP4F forms in Sprague Dawley rats. Drug Metab Dispos 30, 1022-1028.
Kiyose C, Saito H, Kaneko K, Hamamura K, Tomioka M, Ueda T & Igarashi O (2001a) Alpha-tocopherol affects the urinary and biliary excretion of 2,7,8-trimethyl-2 (2''-carboxyethyl)-6-hydroxychroman, gamma-tocopherol metabolite, in rats. Lipids 36, 467-472.
Kiyose C, Saito H, Ueda T & Igarashi O (2001b) Simultaneous determination of alpha-, gamma-tocopherol and their quinones in rats plasma and tissues using reversed-phase high-performance liquid chromatography. J Nutr Sci Vitaminol (Tokyo) 47, 102-107.
Kliewer SA (2003) The nuclear pregnane X receptor regulates xenobiotic detoxification. J Nutr 133, 2444S-2447S.
Kluth D, Landes N, Pfluger P, Muller-Schmehl K, Weiss K, Bumke-Vogt C, Ristow M & Brigelius-Flohe R (2005) Modulation of Cyp3a11 mRNA expression by alpha-tocopherol but not gamma-tocotrienol in mice. Free Radic Biol Med 38, 507-514.
Lake BG, Gray TJ, Korosi SA & Walters DG (1989) Nafenopin, a peroxisome proliferator, depletes hepatic vitamin E content and elevates plasma oxidised glutathione levels in rats. Toxicol Lett 45, 221-229.
Landes N, Pfluger P, Kluth D, Birringer M, Ruhl R, Bol GF, Glatt H & Brigelius-Flohe R (2003) Vitamin E activates gene expression via the pregnane X receptor. Biochem Pharmacol 65, 269-273.
Lee CH, Olson P & Evans RM (2003) Minireview: lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors. Endocrinology 144, 2201-2207.
Leonard SW, Gumpricht E, Devereaux MW, Sokol RJ & Traber MG (2005) Quantitation of rat liver vitamin E metabolites by LC-MS during high-dose vitamin E administration. J Lipid Res.
Li YJ & Shaw HM (2007) Pregnenolone and dexamethasone, modulators of cytochrome P450-3A, not increase but reduce urinary alpha-CEHC excretion in rats. Biofactors 31, 67-76.
Liebler DC, Burr JA, Philips L & Ham AJ (1996) Gas chromatography-mass spectrometry analysis of vitamin E and its oxidation products. Anal Biochem 236, 27-34.
Lodge JK, Ridlington J, Leonard S, Vaule H & Traber MG (2001) Alpha- and gamma-tocotrienols are metabolized to carboxyethyl-hydroxychroman derivatives and excreted in human urine. Lipids 36, 43-48.
Lodge JK, Traber MG, Elsner A & Brigelius-Flohe R (2000) A rapid method for the extraction and determination of vitamin E metabolites in human urine. J Lipid Res 41, 148-154.
Ma Y, Sachdeva K, Liu J, Song X, Li Y, Yang D, Deng R, Chichester CO & Yan B (2005) Clofibrate and perfluorodecanoate both upregulate the expression of the pregnane X receptor but oppositely affect its ligand-dependent induction on cytochrome P450 3A23. Biochem Pharmacol 69, 1363-1371.
Maher JM, Aleksunes LM, Dieter MZ, Tanaka Y, Peters JM, Manautou JE & Klaassen CD (2008) Nrf2- and PPAR alpha-mediated regulation of hepatic Mrp transporters after exposure to perfluorooctanoic acid and perfluorodecanoic acid. Toxicol Sci 106, 319-328.
Mahoney CW & Azzi A (1988) Vitamin E inhibits protein kinase C activity. Biochem Biophys Res Commun 154, 694-697.
McCay PB (1985) Vitamin E: interactions with free radicals and ascorbate. Annu Rev Nutr 5, 323-340.
Miller ER, 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ & Guallar E (2005) Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 142, 37-46.
Morinobu T, Yoshikawa S, Hamamura K & Tamai H (2003) Measurement of vitamin E metabolites by high-performance liquid chromatography during high-dose administration of alpha-tocopherol. Eur J Clin Nutr 57, 410-414.
Murray ED, Jr., Wechter WJ, Kantoci D, Wang WH, Pham T, Quiggle DD, Gibson KM, Leipold D & Anner BM (1997) Endogenous natriuretic factors 7: biospecificity of a natriuretic gamma-tocopherol metabolite LLU-alpha. J Pharmacol Exp Ther 282, 657-662.
Mustacich DJ, Leonard SW, Devereaux MW, Sokol RJ & Traber MG (2006) [alpha]-Tocopherol regulation of hepatic cytochrome P450s and ABC transporters in rats. Free Radical Biology and Medicine 41, 1069-1078.
Mustacich DJ, Shields J, Horton RA, Brown MK & Reed DJ (1998) Biliary secretion
of alpha-tocopherol and the role of the mdr2 P-glycoprotein in rats and mice. Arch Biochem Biophys 350, 183-192.
Mustacich DJ, Vo AT, Elias VD, Payne K, Sullivan L, Leonard SW & Traber MG (2007) Regulatory mechanisms to control tissue [alpha]-tocopherol. Free Radical Biology and Medicine 43, 610-618.
Nebert DW & Russell DW (2002) Clinical importance of the cytochromes P450. Lancet 360, 1155-1162.
Omura T, Sato R, Cooper DY, Rosenthal O & Estabrook RW (1965) Function of cytochrome P-450 of microsomes. Fed Proc 24, 1181-1189.
Osumi T, Ishii N, Hijikata M, Kamijo K, Ozasa H, Furuta S, Miyazawa S, Kondo K, Inoue K, Kagamiyama H & et al. (1985) Molecular cloning and nucleotide sequence of the cDNA for rat peroxisomal enoyl-CoA: hydratase-3-hydroxyacyl-CoA dehydrogenase bifunctional enzyme. J Biol Chem 260, 8905-8910.
Osumi T, Ishii N, Miyazawa S & Hashimoto T (1987) Isolation and structural characterization of the rat acyl-CoA oxidase gene. J Biol Chem 262, 8138-8143.
Otterness DM & Weinshilboum R (1994) Human dehydroepiandrosterone sulfotransferase: molecular cloning of cDNA and genomic DNA. Chem Biol Interact 92, 145-159.
Parker RS, Sontag TJ & Swanson JE (2000) Cytochrome P4503A-dependent metabolism of tocopherols and inhibition by sesamin. Biochem Biophys Res Commun 277, 531-534.
Parker RS & Swanson JE (2000) A novel 5''-carboxychroman metabolite of gamma-tocopherol secreted by HepG2 cells and excreted in human urine. Biochem Biophys Res Commun 269, 580-583.
Pelkonen O, Maenpaa J, Taavitsainen P, Rautio A & Raunio H (1998) Inhibition and induction of human cytochrome P450 (CYP) enzymes. Xenobiotica 28, 1203-1253.
Pope SA, Burtin GE, Clayton PT, Madge DJ & Muller DP (2002) Synthesis and analysis of conjugates of the major vitamin E metabolite, alpha-CEHC. Free Radic Biol Med 33, 807-817.
Pope SA, Clayton PT & Muller DP (2000) A new method for the analysis of urinary vitamin E metabolites and the tentative identification of a novel group of compounds. Arch Biochem Biophys 381, 8-15.
Reddy JK & Hashimoto T (2001) Peroxisomal beta-oxidation and peroxisome proliferator-activated receptor alpha: an adaptive metabolic system. Annu Rev Nutr 21, 193-230.
Saito H, Kiyose C, Yoshimura H, Ueda T, Kondo K & Igarashi O (2003) Gamma-tocotrienol, a vitamin E homolog, is a natriuretic hormone precursor. J Lipid Res 44, 1530-1535.
Schultz M, Leist M, Elsner A & Brigelius-Flohe R (1997) alpha-Carboxyethyl-6-hydroxychroman as urinary metabolite of vitamin E. Methods Enzymol 282, 297-310.
Schultz M, Leist M, Petrzika M, Gassmann B & Brigelius-Flohe R (1995) Novel urinary metabolite of alpha-tocopherol, 2,5,7,8-tetramethyl-2(2''-carboxyethyl)-6-hydroxychroman, as an indicator of an adequate vitamin E supply? Am J Clin Nutr 62, 1527S-1534S.
Simon E (1956) Tentative impressions about the efficacy of group therapy in psychosomatic disorders. Acta Med Orient 15, 195-200.
Singh I (1997) Biochemistry of peroxisomes in health and disease. Mol Cell Biochem 167, 1-29.
Small GM, Burdett K & Connock MJ (1985) A sensitive spectrophotometric assay for peroxisomal acyl-CoA oxidase. Biochem J 227, 205-210.
Sontag TJ & Parker RS (2002) Cytochrome P450 omega-hydroxylase pathway of tocopherol catabolism. Novel mechanism of regulation of vitamin E status. J Biol Chem 277, 25290-25296.
Sontag TJ & Parker RS (2007) Influence of major structural features of tocopherols and tocotrienols on their {omega}-oxidation by tocopherol-{omega}-hydroxylase. J. Lipid Res. 48, 1090-1098.
Srinivasan SR, Chow CK & Glauert HP (1990) Effect of the peroxisome proliferator ciprofibrate on hepatic DNA synthesis and hepatic composition following partial hepatectomy in rats. Toxicology 62, 321-332.
Stahl W, Graf P, Brigelius-Flohe R, Wechter W & Sies H (1999) Quantification of the alpha- and gamma-tocopherol metabolites 2,5,7, 8-tetramethyl-2-(2''-carboxyethyl)-6-hydroxychroman and 2,7, 8-trimethyl-2-(2''-carboxyethyl)-6-hydroxychroman in human serum. Anal Biochem 275, 254-259.
Sulzle A, Hirche F & Eder K (2004) Thermally oxidized dietary fat upregulates the expression of target genes of PPAR alpha in rat liver. J Nutr 134, 1375-1383.
Swanson JE, Ben RN, Burton GW & Parker RS (1999) Urinary excretion of 2,7, 8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman is a major route of elimination of gamma-tocopherol in humans. J Lipid Res 40, 665-671.
Tanabe M, Fukushima T, Usui N, Aoyama N, Tsunoda M & Imai K (2004) Intravenous administration of 2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxy chroman (gamma-CEHC) to
rats and determination of its plasma concentration and urinary sodium excretion. Biomed Chromatogr 18, 727-734.
Thurnham DI, Davies JA, Crump BJ, Situnayake RD & Davis M (1986) The use of different lipids to express serum tocopherol: lipid ratios for the measurement of vitamin E status. Ann Clin Biochem 23 ( Pt 5), 514-520.
Torczynski R, Bollon AP & Fuke M (1983) The complete nucleotide sequence of the rat 18S ribosomal RNA gene and comparison with the respective yeast and frog genes. Nucleic Acids Res 11, 4879-4890.
Traber MG (1994) Determinants of plasma vitamin E concentrations. Free Radic Biol Med 16, 229-239.
Traber MG (2004) Vitamin E, nuclear receptors and xenobiotic metabolism. Arch Biochem Biophys 423, 6-11.
Traber MG, Elsner A & Brigelius-Flohe R (1998) Synthetic as compared with natural vitamin E is preferentially excreted as alpha-CEHC in human urine: studies using deuterated alpha-tocopheryl acetates. FEBS Lett 437, 145-148.
Traber MG & Kayden HJ (1984) Vitamin E is delivered to cells via the high affinity receptor for low-density lipoprotein. Am J Clin Nutr 40, 747-751.
Traber MG, Lane JC, Lagmay NR & Kayden HJ (1992) Studies on the transfer of tocopherol between lipoproteins. Lipids 27, 657-663.
Traber MG, Olivecrona T & Kayden HJ (1985) Bovine milk lipoprotein lipase transfers tocopherol to human fibroblasts during triglyceride hydrolysis in vitro. J Clin Invest 75, 1729-1734.
Traber MG, Siddens LK, Leonard SW, Schock B, Gohil K, Krueger SK, Cross CE & Williams DE (2005) alpha-Tocopherol modulates Cyp3a expression, increases gamma-CEHC production, and limits tissue gamma-tocopherol accumulation in mice fed high gamma-tocopherol diets. Free Radic Biol Med 38, 773-785.
Traber MG & Sies H (1996) Vitamin E in humans: demand and delivery. Annu Rev Nutr 16, 321-347.
Tukey RH & Strassburg CP (2000) Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annu Rev Pharmacol Toxicol 40, 581-616.
Van Rafelghem MJ, Vanden Heuvel JP, Menahan LA & Peterson RE (1988) Perfluorodecanoic acid and lipid metabolism in the rat. Lipids 23, 671-678.
Vanden Heuvel JP (1996) Perfluorodecanoic acid as a useful pharmacologic tool for the study of peroxisome proliferation. Gen Pharmacol 27, 1123-1129.
Vanhooren JC, Baumgart E, Fransen M, Mannaerts GP & Van Veldhoven PP (1996) Mammalian peroxisomal acyl-CoA oxidases. I. Molecular characterization of rat pristanoyl-CoA oxidase. Ann N Y Acad Sci 804, 674-675.
Wagner KH, Kamal-Eldin A & Elmadfa I (2004) Gamma-tocopherol--an underestimated vitamin? Ann Nutr Metab 48, 169-188.
Waxman DJ (1999) P450 gene induction by structurally diverse xenochemicals: central role of nuclear receptors CAR, PXR, and PPAR. Arch Biochem Biophys 369, 11-23.
Wechter WJ, Kantoci D, Murray ED, Jr., D''Amico DC, Jung ME & Wang WH (1996) A new endogenous natriuretic factor: LLU-alpha. Proc Natl Acad Sci U S A 93, 6002-6007.
Weimann BJ & Weiser H (1991) Functions of vitamin E in reproduction and in prostacyclin and immunoglobulin synthesis in rats. Am J Clin Nutr 53, 1056S-1060S.
Weinshilboum R & Aksoy I (1994) Sulfation pharmacogenetics in humans. Chem Biol Interact 92, 233-246.
Weiser H & Vecchi M (1981) Stereoisomers of alpha-tocopheryl acetate--characterization of the samples by physico-chemical methods and determination of biological activities in the rat resorption-gestation test. Int J Vitam Nutr Res 51, 100-113.
Wolf CJ, Takacs ML, Schmid JE, Lau C & Abbott BD (2008) Activation of mouse and human peroxisome proliferator-activated receptor alpha by perfluoroalkyl acids of different functional groups and chain lengths. Toxicol Sci 106, 162-171.
Wu JH & Croft KD (2007) Vitamin E metabolism. Mol Aspects Med 28, 437-452.
Yoshida Y & Niki E (2002) Antioxidant effects of alpha- and gamma-carboxyethyl-6-hydroxychromans. Biofactors 16, 93-103.
Yoshikawa S, Morinobu T, Hamamura K, Hirahara F, Iwamoto T & Tamai H (2005) The effect of [gamma]-tocopherol administration on [alpha]-tocopherol levels and metabolism in humans. Eur J Clin Nutr 59, 900-905.
You CS, Sontag TJ, Swanson JE & Parker RS (2005) Long-chain carboxychromanols are the major metabolites of tocopherols and tocotrienols in A549 lung epithelial cells but not HepG2 cells. J Nutr 135, 227-232.
Zomer AW, van Der Burg B, Jansen GA, Wanders RJ, Poll-The BT & van Der Saag PT (2000) Pristanic acid and phytanic acid: naturally occurring ligands for the nuclear receptor peroxisome proliferator-activated receptor alpha. J Lipid Res 41, 1801-1807.