在肺結核病患中去毒蛋白基因之多型性和治療副作用的關係研究

The Detoxification Protein Gene Polymorphisms in Adverse Drug Reactions among Patients with Pulmonary Tuberculosis

黃瑞明(Rui-Ming Huang) ； 簡順添(Shun-Teien Chien) ； 吳佩芬(Pei-Fen Wu) ； 姜泰安(Tai-An Chiang)

《中南盟研究年刊》 3卷1期 (2010/03) Pp. 55-62

https://doi.org/10.6850/JCSMA.201003_3(1).0006

摘要

目的：人體中以氧化、鍵結與運送三大方式來代謝藥物，其中氧化方式以CYP450酵素為主，而以UGT酵素鍵結葡萄糖醛酸來增加藥物水溶性提高代謝率，綜觀現今研究多以氧化酵素為主，針對UGT酵素代謝肺結核藥物之關聯性則未有系統性之研究。方法：本研究針對肺結核病患中去毒蛋白基因(UGT)之多型性和治療副作用的關係分析，本計畫依原定規劃收集50名肺結核病患經診斷有治療副作用肝傷害（病例組）；50名肺結核病患經診斷沒有治療副作用肝傷害（對照組）；最後經資料配對與篩除資料不完整個案後總計68名個案（30名病例組、38名對照組）進入基因多型性與治療副作用分析。結果：結果顯示病患帶有UGT1A7(上標 *)1/(上標 *)2基因型者較野生型(UGT1A7(上標 *)1/(上標 *)1)者得到治療副作用肝傷害危險比(Odds Rdtio; OR)高出3.33倍(95% CI=1.04-10.59)，而病患帶有UGT1A7(上標 *)1/(上標 *)3基因型者較野生型(UGT1A7(上標 *)1/(上標 *)1)者得到治療副作用肝傷害危險比(0R)高出7.14倍(95%CI=1.12-45.51)。結論：本研究顯示病患帶有UGTIA7(上標 *)1/(上標 *)2與(上標 *)1/(上標 *)3基因型者較野生型(UGT1A7(上標 *)1/(上標 *)1)者得到治療副作用肝傷害危險為高且達統計顯著意義，應為UGT1A7基因型改變導致酵素代謝功能降低延遲肺結核藥物代謝時聞，進而增加藥物對肝臟的實質傷害，本研究為全世界第1篇針對去毒蛋白基因(UGT1A7)之多型性在抗肺結核藥物治療副作用中所扮演的角色所做的研究，可有效解釋先前相關研究中30北以上在抗肺結核藥物治療副作用之不明原因，可成為防治肺結核研究中之重要參考文獻。未來應用藥物基因體學，可由人體基因之檢測，來了解何種基因型的人易產生抗肺結核治療副作用，從而避免服用或減量服用某種抗結核藥物，或加強肝功能之追蹤以減少抗肺結核藥物治療副作用發生。

關鍵字

肺結核 ； 去毒蛋白基因 ； 多型性 ； 治療副作用

並列摘要

Objectives. The three phases of detoxification are oxidation, conjugation, and transportation. The oxidation reaction is mainly catalyzed by cytochrome P450 (CYP), whi1e UDP-glucuronosyltransferase (UGT) is the major enzyme involved in the conjugation reaction, with a number of proteins responsible for the transportation of toxic metabolites. Of these three detoxification phases, oxidation has been the most studied, whi1e conjugation and transportation are newer areas of research focus in the 21st century.
Methods. This study investigate the relationships between detoxification protein gene polymorphisms and adverse drug effects of anti-tuberculosis disease drugs. 50 TB infected cases with adverse drug effects and 50 TB infected cases without adverse drug effects were inc1uded. 68 TB infected cases (30 cases and 38 controls) are inc1uded in analysis and some samples are exc1ude due to the incompetence of demography data.
Results. Genotypes of UGT 1A7(superscript *)1/(superscript *)2 may increase the risk and severity of anti-TB drug-induced hepatitis as the odds ratio (OR) are 3.33 (95% CI=1.04-10.59), and genotypes of UGT 1A7(superscript *)1/(superscript *)3 may increase the risk and severity of anti-TB drug-induced hepatitis as the odds ratio (OR) are 7.14 (95% CI=1.12-45.51).
Conclusions. This study indicated that the UGT 1A7 polymorphism may correlate the drug-related adverse drug effects among TB patients in Taiwan. Checking liver enzymes and detoxification genotype before treatment and regular monitoring liver enzymes during treatment are highly recommended. Application of pharmacogenetics or pharmacogenomics, such as assessing UGT genetic polymorphism, may help prevent this hepatotoxicity. The results from these investigations wi11 prove to be helpful for understanding the adverse drug effects of TB and provide novel insights in controlling mycobacterial infection in our population.

並列關鍵字

Pulmonary tuberculosis ； detoxification protein gene ； polymorphisms ； adverse drug effects