輔酶Q10對肝癌病人氧化壓力與發炎之評估

根據世界衛生組織及臺灣衛生福利部資料顯示，肝細胞癌（hepatocellular carcinoma）不論在世界上或台灣均佔癌症死亡的第二位。已有研究指出較高的氧化壓力及發炎現象會導致粒線體失能、慢性肝臟發炎、甚至致癌。對於原發性肝細胞癌，肝切除手術目前為主要的治癒性治療之一。在手術期間及術後，人體會承受生理壓力，進而影響發炎現象、內分泌、新陳代謝、及免疫反應。肝細胞癌的病患接受手術切除治療，氧化壓力及發炎反應亦會影響術後併發症及長期預後。輔酶Ｑ10為參與粒線體電子傳遞鏈生成三磷酸腺苷中重要脂溶性營養素。輔酶Q10亦是細胞內抗氧化劑，可以保護細胞膜磷脂質、粒線體膜蛋白質、以及低密度脂蛋白膽固醇不受自由基的氧化傷害。然而，目前並沒有研究探討肝癌病人手術前後輔酶Q10與氧化壓力及發炎之相關性。本研究首先利用觀察性實驗，探討肝癌病人手術前後血中輔酶Q10濃度、氧化壓力及發炎反應。研究對象為第一、二期病患。於肝切除術前及術後4週檢測血中輔酶Q10及維生素E濃度、丙二醛、超氧化物歧化酶、過氧化氫酶、穀胱甘肽過氧化物酶、及發炎指標（高敏感度C-反應蛋白、腫瘤壞死因子-α、介白素-6）。研究發現，這些病患的術前血中輔酶Q10濃度低於正常值（0.5至1.7μM），且術後更為下降（中位數濃度，術前：0.32 μM，術後：0.28 μM，p < 0.01）。超氧化物歧化酶、過氧化氫酶、穀胱甘肽過氧化物酶、及發炎指標（高敏感度C-反應蛋白、腫瘤壞死因子-α及介白素-6）術後均顯著上升，而丙二醛術後會下降。輔酶Q10濃度與維生素E濃度、穀胱甘肽過氧化物酶成正相關（β = 9.85，p < 0.01；β = 6.43，p = 0.04）。比較手術前後丙二醛濃度變化與輔酶Q10、超氧化物歧化酶、過氧化氫酶、穀胱甘肽過氧化物酶等濃度變化是成負相關。手術前後輔酶Q10濃度變化與高敏感度C-反應蛋白、介白素-6濃度變化亦成顯著負相關。本研究進一步設計隨機對照介入型實驗，探討給予手術後肝癌病人輔酶Q10補充劑對其氧化壓力及發炎之影響。受試者單盲隨機分派至安慰劑組及輔酶Q10組（每日300毫克）。連續介入12週，測量項目與觀察性研究相同。輔酶Q10介入後，病患之輔酶Q10濃度、超氧化物歧化酶、過氧化氫酶、穀胱甘肽過氧化物酶均顯著升高且顯著高於安慰劑組。輔酶Q10介入後，輔酶Q10組血中丙二醛濃度顯著下降且顯著低於安慰劑組。於輔酶Q10組的病患中，介入前後血漿輔酶Q10濃度變化與維生素E（β = 1.33，p = 0.01）、超氧化物歧化酶（β = 2.57，p = 0.02）、過氧化氫酶（β = 4.47，p < 0.01）、穀胱甘肽過氧化物酶（β = 3.53，p = 0.03）等濃度變化成正相關。介入前後血漿輔酶Q10濃度變化與丙二醛濃度變化成負相關（β = -0.29，p = 0.02）。本研究發現肝癌病人接受肝腫瘤切除手術後會有較低的輔酶Q10濃度及較高的發炎反應；術後肝癌病人藉由每日300毫克的輔酶Q10補充可增加其抗氧化力、降低氧化壓力與發炎指標濃度。由於肝癌病人有較高的氧化壓力、較高的發炎現象、及較低的輔酶Q10濃度，故我們建議輔酶Q10補充劑可做為其術後輔助治療，以提升其術後抗氧化力與降低發炎反應。

According to data from World Health Organization and Ministry of Health and Welfare in Taiwan, liver cancer is the second leading cause of cancer deaths both worldwide and in Taiwan. Studies have shown that an increment in oxidative stress and inflammation may result in mitochondrial dysfunction, chronic hepatitis, and subsequent hepatocarcinogenesis. Surgical resection is the major curative treatment for patients with primary hepatocellular carcinoma (HCC). A physiological stress response, involving activation of inflammatory, endocrine, metabolic, and immunological mediators, occurs during and after surgery. The increase in oxidative stress and inflammation may also have an impact on post-operative complications and long-term prognosis in patients with HCC after liver resection. Coenzyme Q10 is a lipid-soluble nutrient that is a key component of the mitochondrial respiratory chain essential for adenosine triphosphate synthesis. Coenzyme Q10 is also an intracellular antioxidant that can protect membrane phospholipids, mitochondrial membrane proteins, and low density lipoprotein-cholesterol from free radical-induced oxidative stress. To the best of our knowledge, no studies have investigated the relationships of oxidative stress, inflammation, and coenzyme Q10 in patients with HCC before and after surgery. We conducted an observational study to elucidate differences in oxidative stress, antioxidant capacities, inflammation status, and coenzyme Q10 levels in patients with HCC before and after surgery. We recruited patients with HCC who were classified as stages I and II. Blood samples were collected before surgery and after surgery and parameters including plasma coenzyme Q10, vitamin E, malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and inflammatory markers (high sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were assessed. We found that the concentrations of coenzyme Q10 in patients with HCC were lower than reference values (0.5 to 1.7 μM) and were significantly decreased after surgery (median level, before surgery: 0.32 μM, after surgery: 0.28 μM, p < 0.01). The level of SOD, CAT, GPx, hs-CRP, TNF-α, and IL-6 increased in patients with HCC after surgery. The level of MDA decreased after surgery. Changes in MDA levels were negatively correlated with the changes in the level of coenzyme Q10, SOD, CAT, and GPx. Change in coenzyme Q10 levels were negatively correlated with the changes in the levels of hs-CRP and IL-6. We then conducted an intervention study to investigate the effects of coenzyme Q10 supplementation on oxidative stress and inflammation in patients with HCC after surgery. Patients were single-blinded and randomly assigned to placebo or coenzyme Q10 groups (300 mg/day). Intervention for 12 weeks was arranged and the measures items were the same as the observation study. The levels of coenzyme Q10, SOD, CAT, and GPx significantly increased in patients of coenzyme Q10 group after 12-week intervention. The levels of coenzyme Q10, SOD, CAT, and GPx were also significantly higher in patients of coenzyme Q10 group than those in patients of placebo group after intervention. The MDA significantly decreased in patients after 12-week coenzyme Q10 intervention. The MDA was also significantly lower in patients of coenzyme Q10 group than those in the placebo group. There were positive correlations between the changes in the level of plasma coenzyme Q10 and the changes in the levels of vitamin E (β = 1.33，p = 0.01), SOD (β = 2.57，p = 0.02), CAT (β = 4.47，p< 0.01), and GPx (β = 3.53，p = 0.03) after 12-week intervention. There was a negative correlation between the change in the levels of coenzyme Q10 and MDA (β = -0.29，p = 0.02) in patients of coenzyme Q10 group after 12-week intervention. Patients with HCC had significantly lower levels of coenzyme Q10 and higher inflammatory status after surgery. We suggest that coenzyme Q10 supplementation could be applied as a complementary treatment for patients with HCC after surgery, particularly those showing elevated oxidative stress and inflammation.