| 摘要: | 研究指出攝取薏苡（Coix lachrymal-jobi L.var. mayuen Stapf ）具有許多預防慢性病的好處，而薏仁麩皮脂溶性成分具有降低血脂及抑制大腸癌及肺癌的功能。為探討薏仁麩皮乙醇萃取物（adlay bran ethanolic extract；ABE）與藥物是否會產生交互作用及長時間攝取ABE對組織中藥物代謝酵素及氧化壓力之影響，進行以下三個實驗。實驗一：以HPLC/MS進行ABE之成份分析與鑑定，並探討ABE對體外大鼠及人類肝臟微粒體中CYP酵素活性之抑制作用。另外再評估單一劑量ABE的給予對口服及靜脈注射五種CYP酵素（CYP1A2：theophylline， CYP2C：diclofenac， CYP2D： dextromethophen， CYP2E1： chlorzoxazone 及 CYP3A：diltiazem）受質藥物之藥物動力學的影響。實驗結果顯示ABE中含有16種已知酚類化合物與3種植物固醇，並發現肝臟微粒體中CYP2C、3A、2D、2E1及1A1活性均會受到ABE顯著的抑制（大鼠IC50：18.0～57.4 μg/mL; 人類IC50：15.4~44.8 μg/mL），然而ABE對CYP1A2活性的抑制則較弱（IC50>100 μg/mL）；在藥物動力學方面，單一劑量ABE的給予會提高口服theophylline及dextromethorphan之血中藥物濃度曲線下面積（AUC: area under the plasma drug concentration），但若給予以靜脈注射上述五種CYP受質藥物，單一劑量口服ABE並不改變五種藥物之藥物動力學。實驗二：探討大鼠攝取ABE飲食對上述五種CYP受質藥物之藥物動力學的影響，並測定肝臟中主要代謝這五種CYP受質藥物之酵素活性，將大鼠分為控制組及餵食20％ABE組，結果發現攝取含ABE飼料七天後，會提高口服theophylline及chlorzoxazone之血中AUC；在肝臟CYP酵素活性方面，只有CYP2C酵素活性與蛋白質表現會被抑制。實驗三：探討大鼠餵食ABE四週後對大鼠肝臟、腎臟及肺臟中藥物代謝酵素及氧化壓力之影響，將大鼠分為控制組、5％及10％ABE組，結果顯示5%及10%ABE飲食會顯著降低肝臟CYP2C、3A、2D及1A1及肺臟CYP1A1之酵素活性，且CYP蛋白質含量變化與其酵素活性一致性，而10% ABE則會顯著抑制肝臟CYP2E1及CYP1A2並提升肺臟GST之酵素活性；在抗氧化物質與酵素活性方面，雖ABE不改變肝臟中之抗氧化物質與抗氧化酵素活性，但ABE會顯著提升肺臟GSH含量、GSH/GSSG比例、GSH peroxidase和GSH reductase活性，也會提高NQO-1 及HO-1蛋白質表現。由以上結果顯示ABE會抑制肝臟CYP酵素活性，而當ABE與口服藥物共服時可能會增加藥物血中濃度，此影響作用可能會受到ABE服用時間的增加而改變；另外，長期攝取ABE後會明顯降低肝中CYP酵素與蛋白質表現，提高肺臟GSH及抗氧化酵素活性，並降低肺臟之氧化壓力。
Studies have shown that adlay（Coix lachrymal-jobi L.var. mayuen Stapf） has beneficial effects on the prevention of many diseases. The lipopholic components of adlay bran have been demonstrated to have plasma lipids-lowering effects and reduce carcinogenesis in colon and lung cancer cell lines. To investigate whether the adlay bran ethanolic extract (ABE) can cause drug interactions and to evaluate the long-term administration of ABE on drug-metabolizing enzymes and oxidative stress in tissues, three experiments were conducted. Experiment I: HPLC/MS system was used to identify the components in ABE. The inhibitory effect of ABE on CYP enzymes activities in rat and human liver microsomes were determined. In addition, the effect of single oral dose of ABE on the pharmacokinetics of five CYP probe drugs (CYP1A2: theophylline, CYP2C: diclofenac, CYP2D: dextromethophen, CYP2E1: chlorzoxazone and CYP3A: dilitiazem) administered orally or intravenously in rats were also evaluated. Experiment II: This study was to evaluate the short-term administration (20% ABE in the diet for 10 days) of ABE on the pharmacokinetics of five CYP probe drugs and the modulations of ABE on CYP enzymes in liver. Experiment III: This study was to understand the long-term administration (5 and 10% ABE in the diet for 4 weeks) of ABE on drug-metabolizing enzymes and oxidative stress in liver, kidney and lung tissues. Results show that 16 phenolic compounds and 3 phytosterols were identified in ABE. ABE inhibited CYP3A, 2C, 2D, 2E1 and 1A1 enzyme activities in both rat (IC50: 18.0-57.4 μg/mL) and human (IC50: 15.4-44.8 μg/mL) liver microsomes. However, ABE showed relative weak inhibition (IC50>100 μg/mL) on CYP1A2 activity in both rat and human liver microsomes. ABE increased the area under the curve (AUC) of plasma theophylline and dextromethorphan when co-administrated orally but not intravenously with five CYP probe drugs, indicating the drug interactions might be occurred in the small intestine. Furthermore, rats were fed with 20% ABE for 7 days increased the AUC of plasma theophylline and chlorzoxazone and the hepatic CYP2C enzyme activity and protein levels were reduced after 10 days of ABE treatment. Finally, rats fed the ABE-containing diets for 4 weeks reduced CYP3A, 2C, 2D and 1A1 enzyme activities and protein levels in liver and decreased CYP1A1 enzyme activity and protein level in lung. Moreover, higher GSH level, GSH/GSSG ratio, GSH-Px, GSH-Rx and GST activities and NQO-1 protein levels were noted in lung after the ABE treatment. Results from our data indicate that ABE can inhibit several CYP enzymes activities in the liver and this impact is prominent after long-term ABE administration. When co-administrated with certain drugs, ABE may increase systemic drugs exposure and this effect may be also changed by the duration of ABE treatment. Long-term administration of ABE may reduce hepatic CYP enzymes and oxidative stress in lung. |
