以計算方法探討抗氧化能力在補陽類中藥的補益機轉中之角色

Abstract

補益類中藥分為四類：補陰（Yin-nourishing）、補陽（Yang-invigorating）、補氣（Qi-invigorating）以及補血（Blood-enriching）。補陽類與補陰類中藥的特性，目前已知分別為刺激ATP的產生（ATP generation）以及免疫的調節作用（immunomodulatory activity）。然而，在補陽藥中卻發現了高度的抗氧化能力，而抗氧化能力被認為是一種陰的特性。這不合直覺，並且一直是個不解之謎。 在尋找補陽與補陰本質的過程中，在補陽藥裡並未找到共同的化合物，亦即能代表補陽作用的化合物。在我們使用支持向量機（SVM）的機器學習方法中，有一衍伸性的特徵，也就是每單位酚類化合物的ex vivo（生物組織內、生物體之外）的抗氧化能力，可用來區分補陽藥與補陰藥。這顯示補陽藥、補陰藥本質上的差別，是在其單位抗氧化物質的ex vivo抗氧化能力。為了探討在粒線體中抗氧化能力以及生產ATP兩者之間的因果關係，以經過驗證之粒線體數學模型進行了模擬實驗，其模型範圍是粒線體的能量流轉以及自由基的代謝。粒線體系統的數學模型及代謝控制分析（MCA）之結果均指出，抗氧化作用對於ATP產生速率的影響有限。 本研究測試了抗氧化能力與產生ATP的因果關係；提出了一個全新的生化特徵，可用以區分補陽類與補陰類中藥；並且提出了補陽、補陰類中藥在中醫藥典中之所以被分為該類的可能原因。本研究的結果也顯示，現代中醫藥研究若要發掘出中醫藥的內在意義，必須築基於足夠的細胞或生理背景上。

Chinese tonifying herbs are classified into four categories: Yin-nourishing, Yang-invigorating, Qi-invigorating and Blood-enriching. Yang- and Yin-tonifying herbs are known to promote ATP-generation and exhibit immunomodulatory activity respectively. However, the high antioxidant activity, a supposedly Yin property, in Yang-tonifying herbs was counter-intuitive and remained an unresolved question. In search of the essence of being Yang- and Yin-tonifying, common compounds present in and thus representative of Yang-tonifying herbs were not found. In our machine learning approach using support vector machine (SVM), the derived feature of ex vivo antioxidant activity divided by unit phenolic content was able to distinguish Yang- from Yin-tonifying herbs, suggesting that it is ex vivo antioxidant activity per unit antioxidants that is essentially different between Yang- and Yin-tonifying herbs. To characterize the causal relationship between antioxidant activity and ATP generation within mitochondria, simulations were performed using a validated mathematical model of mitochondrial energetics with ROS metabolism. Both mathematical modeling and metabolic control analysis (MCA) of the mitochondrial system showed a limited influence of antioxidation on ATP generation rate. In the present study, the causal relationship between antioxidant activity and ATP-generation is examined, a novel biochemical feature distinguishing between Yang- and Yin-tonifying herbs presented, and a possible explanation of Yang- and Yin-tonifying herbs being categorized as such in TCM pharmacopoeia proposed. Results from this study also suggest that modern TCM investigations, in terms of TCM’s essence, should be fruitful only if they are based on sufficient cellular or physiological context.