尿苷雙磷酸葡萄糖醛酸基轉移酶1A1 (UGT1A1)基因型與抗結核藥物治療期間肝損傷之關聯研究

The Correlation between the Genotypes of UDP-Glucuronosyl Transferase 1A1 (UGT1A1) and Liver Injury during Antituberculosis Therapy

張瑞家(JUI-CHIA CHANG)

指導教授 ： 陳香吟

臺北醫學大學/藥學院/藥學研究所/碩士(2007年)

摘要

目前已知，第一線抗結核藥物治療期間肝損傷之發生率約為20％。第一線抗結核藥物誘發肝毒性的相關危險因子包括：年齡、性別、營養狀態不良、酗酒、B 型或C 型肝炎感染、HIV感染與基因。尿苷雙磷酸葡萄糖醛酸基轉移酶1A1（UGT1A1）是代謝膽紅素的主要酵素，且其亦參與irinotecan等藥物之代謝。UGT1A1基因變異與未結合型高膽紅素血症，及irinotecan誘發之藥物不良反應有相關，但尚未有UGT1A1基因變異的族群，在接受抗結核藥物治療期間發生肝損傷之研究。
本研究主要目的為：（1）針對UGT1A1 基因變異（UGT1A1*6, UGT1A1*27, UGT1A1*28, UGT1A1*(1091) alleles）與基因型，分析其在抗結核藥物治療期間，發生肝損傷與未發生肝損傷的結核病病患身上之分布情形；（2）研究年齡、性別與UGT1A1 基因變異是否為抗結核藥物治療期間發生肝損傷之危險因子。次要目的為：比較帶有UGT1A1 野生型與UGT1A1基因變異的病患在臨床表現之差異。
本研究共納入97名於2005年十二月至2007年四月間，在台北市立萬芳醫院接受第一線抗結核藥物治療之病患，參與研究的97名病患中，有16名於抗結核藥物治療期間發生肝損傷。本研究採病患之全血檢體3 mL，利用PCR-RFLP與DHPLC的方式，檢測UGT1A1*6, UGT1A1*27, UGT1A1*28, UGT1A1*(1091) 共四個alleles，並回溯病患的病歷資料。研究結果發現年齡較大（odds radio：1.043, 95％ CI：1.008-1.080）且同時帶有UGT1A1*27 與UGT1A1*28 alleles（odds radio：21.05, 95％ CI：1.251-354.2）者，為抗結核藥物治療期間發生肝損傷之高危險族群；UGT1A1*（1091 C to T）allele為台灣族群特有之基因變異，在本研究中出現頻率約為1.0％；UGT1A1基因變異組在肺外結核發生率與治療前total bilirubin檢驗基準值均高於UGT1A1野生型組。因此，UGT1A1基因變異與抗結核藥物治療期間發生肝損傷之間的關聯值得進一步探討研究。

關鍵字

尿苷雙磷酸葡萄糖醛酸基轉移酶1A1 ； 抗結核藥物治療 ； 肝損傷

並列摘要

The incidence rate of liver injury for the first-line antituberculosis therapy is about 20％. The relative risk factors of first-line antituberculosis drug-induced hepatotoxicity include age, gender, malnutrition, alcohol abuse, hepatitis B and C, HIV infection and genetics. UDP-Glucuronosyl Transferase 1A1 (UGT1A1) is the major enzyme responsible for the metabolism of bilirubin, as well as irinotecan and other drugs. There are many studies concerning that the genetic variations of UGT1A1 are associated with unconjugated hyperbilirubinemia, and irinotecan-induced adverse drug reactions; however, there is no studies to investigate the association of liver injury during antituberculosis therapy and UGT1A1 genetic variations.
The primary objective of the current study was to analyze the distribution of different UGT1A1 genetic variations（UGT1A1*6, UGT1A1*27, UGT1A1*28, UGT1A1*(1091) alleles）in tuberculosis patients with or without liver injury during antituberculosis therapy. Risk analysis of patients’ characteristics was also performed. The secondary objective was to determine whether the clinical manifestations differ between subjects with UGT1A1 wild and mutate genotypes .
Ninety-seven subjects on first-line antituberculosis therapy from December 2005 to April 2007 in Taipei Municipal WanFang Hospital were included, sixteen of which were encountered liver injury. Whole blood（3 mL）from each patient were analyzed for UGT1A1*6, UGT1A1*27, UGT1A1*28, UGT1A1*(1091) alleles by the PCR-RFLP and DHPLC method. Their medical records were also reviewed. The results showed that the elderly（odds radio：1.043, 95％ CI：1.008-1.080）with UGT1A1*27 and UGT1A1*28 alleles（odds radio：21.05, 95％ CI：1.251-354.2）are susceptible population to liver injury. The frequency of a newly identified allele UGT1A1*（1091 C to T）was about 1％ in the study group. The extrapulmonary tuberculosis ratio and pretreatment total bilirubin level were also higher in the UGT1A1 mutate genotype group. Further studies regarding the correlation of UGT1A1 gene variations and liver injury are warranted.

並列關鍵字

UGT1A1 ； Antituberculosis Therapy ； liver injury

參考文獻

12. 行政院衛生署疾病管制局. 結核病診治指引第二版. 台北: 行政院衛生署疾病管制局; 2006.

104. 邱千芳, 蘇世斌, 林勤益. 臨床上常見的無症狀高膽紅素血症－吉爾伯特症狀群. 基層醫學. 2006;21(4):81-85.

149. 高郁雯. 預測抗結核藥物治療期間肝毒性之評分系統的驗證 台北: 藥學研究所, 台北醫學大學; 2007.

1. Saukkonen JJ, Cohn DL, Jasmer RM, et al. An Official ATS Statement: Hepatotoxicity of Antituberculosis Therapy. Am J Respir Crit Care Med. Oct 15 2006;174(8):935-952.

3. Huang YS. Genetic polymorphisms of drug-metabolizing enzymes and the susceptibility to antituberculosis drug-induced liver injury. Expert Opin Drug Metab Toxicol. Feb 2007;3(1):1-8.