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尿苷

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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

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, UGT1 A1*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 U GT1A1 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 ： 1.251-3 54.2 ）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。

(2)

The Correlation between the Genotypes of UDP-Glucuronosyl Tra nsferase 1A1 (UGT1A1) and Liver Injury during Antituberculosis T

herapy

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 th e major enzyme responsible for the metabolism of bilirubin, as well as irinotecan and other drugs. There ar e many studies concerning that the genetic variations of UGT1A1 are associated with unconjugated hyperb ilirubinemia, 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 var iations （ UGT1A1*6, UGT1A1*27, UGT1A1*28, UGT1A1*(1091) alleles ） in tuberculosis patients wit h 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 su bjects with UGT1A1 wild and mutate genotypes .

Ninety-seven subjects on first-line antituberculosis therapy from December 2005 to April 2007 in Taipei M unicipal 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*(109 1) alleles by the PCR-RFLP and DHPLC method. Their medical records were also reviewed. The results sh owed that the elderly （ odds radio ： 1.043, 95 ％ CI ： 1.008-1.080 ） with UGT1A1*27 and UGT1A 1*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 UGT1

A1 mutate genotype group. Further studies regarding the correlation of UGT1A1 gene variations and liver

injury are warranted.

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