人類有機陰離子運輸器OATP1B1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 Human Organic Anion Transporting Polypeptide 1B1 (OATP1B1) and Liver Injury during Antituberculosis Therapy

陳香郿(Hsiang-Mei Chen)

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)

https://doi.org/10.6831/TMU.2007.00021

摘要

肝損傷是第一線抗結核藥物治療期間最常見的副作用。造成肝損傷的危險因子很多，包括年齡、性別、營養狀態、飲酒、病毒性肝炎以及基因。代謝藥物的酵素發生基因變異已被證實在抗結核藥物治療期間會增加肝損傷的發生率。 然而，最近研究發現在人體內運輸物質的人類有機陰離子運輸器OATP1B1 (Human Organic Anion Transporting Polypeptide 1B1，OATP1B1)和rifampin進入肝臟過程有關。OATP1B1運輸能力根據基因變異而有所不同，被運輸至肝臟的藥量也就因人而異。OATP1B1基因型具有種族差異性，目前在台灣，OATP1B1基因型和抗結核藥物治療期間肝毒性之關聯性則尚未有相關研究。因此，研究OATP1B1基因變異是否會影響rifampin運輸進而導致肝損傷是非常重要的。
本研究主要目的為探討OATP1B1基因型分布在發生肝損傷病患與未發生 肝損傷之對照組中的差異。次要目的為比較肝功能檢驗值於OATP1B1野生型 與變異型之間的差異。本研究共納入97位於台北市立萬芳醫院診斷為結核病之病患，回溯病歷資料並同時收集周邊血液檢體，以PCR-RFLP方式分析檢體，檢測OATP1B1*1b、OATP1B1*5及OATP1B1*15共三個基因變異。研究結果顯示，對偶基因出現頻率以OATP1B1*1b在本研究族群比例最高(64.9%)，野生型OATP1B1*1a次之(24.2%)，OATP1B1*5最少(0.5%)。OATP1B1*5通常以OATP1B1*15型態出現(10.3%)。然而，對偶基因組合成不同OATP1B1基因型在肝損傷組與對照組之間的比例並無統計上的差異。因此，本研究結果顯示抗結核藥物治療期間肝損傷發生時，OATP1B1*1b、OATP1B1*5及OATP1B1*15並非統計上具有意義的危險因子，需要更進一步研究證實OATP1B1基因型與肝損傷的關聯性。

關鍵字

肝損傷 ； 抗結核藥物 ； 基因 ； 人類有機陰離子運輸器1B1

並列摘要

Liver injury is the most common side effect during the first-line antituberculosis therapy. There are many risk factors of liver injury, such as age, gender, nutrition, alchol, viral hepatitis and gene. It has been proved that the genetic variations of metabolic enzyme increased the incidence rate of liver injury. However, recent studies showed that Human Organic Anion Transporting Polypeptide 1B1(OATP1B1) which transports substrates in human bodies is related to the distribution of rifampin. It is very important to study if the genetic variations of OATP1B1 affect the distribution of rifampin, and lead to liver injury. The transporting ability of OATP1B1 is genetically variant, and consequently influences the amount of drug transported to liver. The distribution of OATP1B1 genotypes are depended on the ethnics. There are no related studies avalible on the correlation between OATP1B1 genotypes and hepatotoxicity during antituberculosis therapy for Taiwanese population.
The primary aim of this study was to discuss the distribution of OATP1B1 genotypes in patients with and without liver injury. The secondary aim was to compare the liver function between the OATP1B1 wild-type and mutant-type. This study included 97 patients whom diagnosed tuberculosis in Taipei Municipal Wan Fang Hospital. The patients’ medical charts were reviewed and their peripheral blood samples were collected. These samples were analysed by PCR-RFLP (polymerase chain reactions- restriction fragment lenth polymorphism) to classify into the genotypes OATP1B1*1b, OATP1B1*5 and OATP1B1*15. This study showed that the allele frequency of the study population, OATP1B1*1b is the highest (64.9%), wild type-OATP1B1*1a is intermediate (24.2%), and OATP1B1*5 is the lowest (0.5%). OATP1B1*5 usually coexisted with OATP1B1*1b, which was classified as OATP1B1*15. However, the distribution of different OATP1B1 genotypes between the groups with and without liver injury are not statistically significant. OATP1B1*1b, OATP1B1*5 and OATP1B1*15 were not statistically significant risk factors of liver injury during antituberculosis therapy . Further studies are warranted to investigate the correlation between the genotypes of OATP1B1 and liver injury during antituberculosis therapy.

並列關鍵字

liver injury ； antituberculosis drug ； gene ； OATP1B1

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