TCH-3511抑制細菌β-葡萄醣醛酸苷酶可預防家族性腺瘤性息肉病腸癌發生，過程中腸道菌群的變化

Inhibition of bacterial β-glucuronidase by TCH-3511 prevents intestinal microbiota changes during intestinal tumorigenesis in Familial Adenomatous Polyposis

黃信凱

結腸直腸癌 ； 致癌物質 ； 葡萄醣醛酸化 ； 葡萄醣醛酸 ； TCH-3511抑制劑 ； Colorectal cancer ； carcinogen ； glucuronidation ； β-glucuronidase ； TCH-3511 inhibitor ； AOM

高雄醫學大學醫學研究所碩士班學位論文

2020年

碩士

鄭添祿

繁體中文

現代人因飲食西化的改變且缺乏攝取足夠的纖維素，使得結腸直腸癌的發生率居高不下，且發生的年齡有逐漸下降的趨勢。當人體吃進有毒的致癌物質，會藉由肝臟的解毒路徑代謝致癌物質。肝臟葡萄醣醛酸化是人體主要的代謝途徑，致癌物質藉由葡萄醣醛酸鍵結來降低毒性，此類的化合物可藉由兩個途徑代謝，(一) 進入血液中，並循環到腎臟，從尿液中排出，(二) 從膽汁中排出，進入腸道，被食物中的纖維質吸附，變成糞便排出。然而在第二個途徑時，當化合物進入到腸道後，會被腸道菌所表現的葡萄醣醛酸酶水解而恢復毒性，進而破壞腸道細胞造成腸道毒性，腸道經長久的刺激進而導致腸道腫瘤的生成。在本研究中，我們使用TCH-3511抑制劑，可作為腸道菌葡萄醣醛酸酶專一性的抑制劑，並使用致癌劑Azoxymethanol (AOM)誘發腸道息肉的生成，觀察TCH-3511抑制劑是否能有效降低小鼠腸道葡萄醣醛酸酶活性，以降低息肉的生長，藉此來預防大腸癌的發生。

Westernization of diets and the transformation of food systems and lack of adequate fiber intake have led to a high incidence of colorectal cancer, and the age of the disease has a gradual downward trend. When the human eats toxic carcinogens, it will metabolize carcinogens through the liver's detoxification pathway and hepatic glucuronidation is the main metabolic pathway in humans, and carcinogens reduce toxicity by glucuronic acid bonding. Such compounds can be metabolized by two pathways, (1) into the blood, and circulate to the kidney, from urine It is discharged from the fluid, (2) It is discharged from the bile, enters the intestinal tract, is absorbed by the fibrous matter in the food, and becomes excrement. However, in the second way, when the metabolite enters the intestine, it will be hydrolyzed by glucuronidase expressed by intestinal bacteria to restore toxicity, thereby destroying intestinal cells and causing intestinal toxicity, forming intestinal tumor . In this study, we used a TCH-3511 inhibitor, which can be used as a specific inhibitor of gut bacteria glucuronidase, and used the carcinogen Azoxymethanol (AOM) to induce the formation of intestinal polyps, and observed TCH-3511 inhibitor Whether it can effectively reduce the activity of glucuronidase in the intestine of mice and reduce the growth of polyps, thereby preventing the occurrence of colorectal cancer.