臺灣博碩士論文加值系統

結核病（Tuberculosis，TB）是全球僅次於愛滋病(Human immunodeficiency virus，HIV)，致死率排名第二的傳染性疾病。WHO估計目前全球約有870萬新發結核病患，且有140萬人死於肺結核，由於治療期程長及藥物副作用等因素，常造成患者藥物中斷、治療失敗或引發抗藥性。
常用第一線抗結核藥物，如：異菸鹼醯胺(isoniazid，INH)、立復黴素(rifampin，RIF)與丙基硫異菸醯胺(pyrazinamide，PZA)均會造成致病率1-36%之肝損傷。臨床證據顯示細胞色素P450 2E1 (CYP2E1)與amidase為導致嚴重肝毒性之重要致病因子；目前對於PZA肝毒性機轉，僅了解相關代謝酵素有amidase與xanthine oxidase，然而是何代謝途徑或代謝物造成肝毒性，或各代謝途徑於人體內所佔比例仍不清楚，甚至無任何相關研究。
本研究目的係針對第一線抗結核藥物，探討其肝毒性可能機轉，並以調控相關代謝酵素改善藥物之肝毒性，更進一步希望找出具抗結核藥物肝毒性高風險之代謝酵素xanthine oxidase基因型，期望應用於臨床診斷預測結核患者是否具高肝毒性之風險，降低患者發生肝毒性風險。研究重點一、調控抗結核藥物代謝酵素CYP2E1以改善藥物肝毒性之研究；二、探討PZA肝毒性作用機轉及改善之研究；三、研究結核病患xanthine oxidase對偶基因多型性與抗結核藥物肝毒性之風險評估。
自111種常用且安全、人體可食用賦型劑與食品中黃酮類純成分化合物，利用人肝與鼠肝微粒體篩選CYP2E1抑制劑，挑選抑制率可達60-88%的HUEXC030 (mannitol)進行小鼠藥效藥動試驗；在腹腔內單獨注射抗結核藥物INH、INH/RIF或INH/RIF/PZA的小鼠，與空白對照組相比，於肝功能指標AST (aspartate aminotransferase)、ALT(alanine aminotransferase)及GSP (Galactose single point method)均產生明顯且有意義的上升( p < 0.005)；肝臟脂質過氧化分析，亦呈現malondialdehyde (MDA)明顯增加、glutathione (GSH)顯著下降(p < 0.005)；因抗結核藥物所引起肝傷害也反映在相對應的肝組織切片上，顯示已成功建立抗結核藥物單方INH、複方INH/RIF與INH/RIF/PZA誘發肝毒性小鼠模式。而此肝損傷現象可被同時併用HUEXC030所改善，所測得肝發炎指標AST、ALT及GSP 均有顯著性地下降，所改善的結果也反映在相對應的肝臟組織，其中以HUEXC030劑量每天每公斤1.67毫克的效果最好，於藥動試驗結果亦顯示，併服HUEXC030確實可抑制小鼠體內CYP2E1活性，但不影響INH和RIF等藥物於小鼠體內吸收，此現象亦反映在抗菌試驗中，HUEXC030不影響INH與RIF之藥效；Rifamate®不併服併服抑制劑HUEXC030於健康受試者藥動學研究結果顯示，HUEXC030不影響INH及其代謝物acetyl-INH、INA與RIF於人體內藥動學變化，代表HUEXC030不影響INH與RIF等藥物在人體內吸收情形，而反應於CYP2E1專一性受質Chlorzoxazone (CZX)藥動學參數分析上，與Rifamate®對照組相比，併用HUEXC030會使血中濃度提高，其Cmax、AUCinfinity顯著增加至對照組的137-141% (p < 0.005)，在CZX代謝物6-OH-CZX藥動學參數分析上，HUEXC030會使其代謝物6-OH-CZX血中濃度降低，其Cmax、AUCinfinity顯著下降至對照組的58-62% (p < 0.005)，顯示mannitol在人體內仍具抑制CYP2E1效果。
另外，在細胞、動物、人體體內試驗證實PZA代謝物PA與5-OH-PA對肝細胞毒性均較PZA的細胞毒性大，PZA各代謝物毒性排列順序為5-OH-PA > PA > PZA > 5-OH-PZA；分析191位服用抗結核藥複方TB患者之尿液，結果亦顯示服用PZA有肝毒性患者尿液中，其毒性代謝物5-OH-PA比例會隨肝毒性的嚴重性而增加 (p < 0.005)；在PZA併服不併服代謝酵素amidase抑制劑HUCHE033(quercetin)於大鼠體內試驗結果，顯示併服HUCHE033試驗組大鼠體內PZA毒性代謝物5-OH-PA含量顯著低於單獨服用PZA對照組( p < 0.005)，且HUCHE033能分別有效降低毒性代謝物5-OH-PA ( p < 0.005)與PA之代謝比率 (p < 0.05)，amidase抑制率約24-37%，顯示HUCHE033可有效降低因PZA所產生之肝毒性，其改善結果亦反應在AST、ALT、GSP與相對應肝組織切片上；在PZA併服不併服HUCHE033於健康受試者體內試驗結果，顯示併服HUCHE033對PZA於健康受試者體內的藥物動力學影響並不顯著，但卻能有效降低PZA毒性代謝物5-OH-PA之原藥物曲線下面積 (p < 0.01)，抑制率約25%，在metabolic ratio分析結果亦顯示HUCHE033能有效降低PZA毒性代謝物5-OH-PA ( p < 0.01)與PA 代謝比例 ( p < 0.01)，抑制率約39%，顯示HUCHE033於人體、大鼠體內同樣具抑制amidase效果，且可降低5-OH-PA、PA等毒性代謝物含量，推論quercetin可能具降低PZA藥物肝毒性之潛力。
PZA主要代謝酵素xanthine oxidase (XO)具基因多型性(gene polymorphism)，對其酵素活性會產生顯著影響，在收集分析451位TB患者基因檢體，其中扣除原本即有肝臟疾病者(40人)，共有411人進行風險分析。結果發現411人中77人因服用抗結核藥物產生肝副作用，比率達到18.7%。若帶有2個 XO SNPs，其中任一個SNP之TB患者，其服用抗結核藥物誘發肝毒性風險顯著高於未帶這2個SNPs患者達1.7-4.8倍，這2個 SNPs 分別為rs1884725 (Odd ratio [OR], 1.71, p = 0.043)與rs2295475 ([OR], 4.32, p = 0.006)，顯示具rs1884725與rs2295475 突變型對偶基因患者較野生型具較高發生肝毒性風險，而這2個基因型在國人的發生頻率達到0.312~0.512，亦即有三成多到五成多的TB患者是屬於服用抗結核藥物誘發肝毒性的高風險群，這是目前文獻未提及過新發現，可給予醫師在治療結核病患用藥處方上之建議與參考。
綜合上述，我們已建立抗結核藥物造成肝毒性之動物模式，並成功自111種常用中篩選了多種CYP2E1及amidase抑制劑，由細胞、動物和臨床深入研究PZA致肝毒性機轉，同時也找出具高肝毒性風險之基因，並進入動物試驗證明抑制CYP2E1及amidase可降低或去除抗結核藥物之肝毒性，並於健康人體內證實此二酵素抑制劑在具抑制效果之下，不影響抗結核藥物濃度及其藥效。

Backgrounds and Aims: Tuberculosis (TB) is the second leading cause of death from an infectious disease worldwide, after the human immunodeficiency virus (HIV). Drug-induced adverse effects: isoniazid (INH), rifampin (RIF) and pyrazinamide (PZA) may induce hepatic injury, incidences various 1-36%. Cytochrome P450 2E1 (CYP2E1) and amidase are thought to contribute to the anti-tuberculosis drugs-induced hepatotoxicity (ATDH). In addition, the severity of PZA-induced hepatotoxicity is no less than that associated with INH or RIF. However, relatively little is known about the hepatotoxicity of PZA. The objectives of this study were to: (1) investigate the mechanism of ATDH and improve the ATDH through metabolic enzymes regulation; (2) to evaluate whether the genetic polymorphisms of xanthine oxidase (XO) influence susceptibility to ATDH.
Methods: We screened 111 known compounds from known pharmaceutical excipients and natural flavonoids compounds as inhibitors of CYP2E1. The hepatotoxic fixed-dose of INH/RIF/PZA were 50/100/250 mg/kg/day, respectively. Hepatotoxicity was assessed by the galactose single point (GSP) method (a US Food and Drug Administration (FDA) recommended quantitative liver function test), liver histopathology, malondialdehyde (MDA) assay, and measurement of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activity. We chose the CYP2E1-specific substrate chlorzoxazone to assess CYP2E1 activity in mice and human. In addition, PZA metabolites were identified and cytotoxicity in HepG2 cells was assessed. Potential PZA and PA hepatotoxicity was then tested in rats. Urine specimens were collected from 191 TB patients and the results were evaluated to confirm whether a correlation existed between PZA metabolite concentrations and hepatotoxicity. This led to the hypothesis that co-administration of amidase inhibitor decreases or prevents PZA (and its metabolites)-induced hepatotoxicity in rats and human. Finally, we included 411 TB patients to evaluate whether the genetic polymorphisms of XO influence susceptibility to ATDH.
Results: Selected CYP2E1 inhibitor, HUEXC030 (mannitol) inhibited CYP2E1 activity by 60% to 88% in HLMs and RLMs in a dose-dependent manner. HUEXC030 diminished or even eradicated INH/RIF-induced hepatotoxicity in mice. Serum AST, ALT and GSP levels were significantly increased 3.8- to 7.8-fold in these mice (p < 0.005), and these levels could be lowered by selected CYP2E1 inhibitors. Moreover, HUEXC030 treatment prevented INH/RIF-mediated lipid peroxidation, as indicated by the reduction in hepatic GSH depletion and MDA formation (p < 0.005). Pharmacokinetic studies with INH/RIF showed that co-treatment with HUEXC030 inhibited CYP2E1 activity but did not affect the absorption of INH and RIF in mice. We also demonstrated the pharmacodynamically effective CYP2E1 inhibitor HUEXC030 had the same inhibitory effect on CYP2E1 in healthy volunteers as well as in mice, with inhibition of up to 58% (p < 0.005). These results implied that above selected CYP2E1 inhibitors have the high potential for use in developing a novel INH/RIF pharmaceutical formulation that does not cause hepatotoxicity and consequently improving the compliance of TB patients taking anti-TB drugs. To determine whether PZA metabolites are responsible for PZA-induced hepatotoxicity, PA and 5-OH-PA are more toxic than PZA. PZA and PA treatment of rats significantly increases AST and ALT activity and GSP levels (p < 0.005). In analysis of PZA metabolites in 191 TB patients’ urine with hepatotoxicity, provides addition evidence support for 5-OH-PA significantly increased the phenomenon (p < 0.005). PA and 5-OH-PA, the metabolites of PZA through amidase catalysis, were more toxic effect than PZA in HepG2 cell. In pharmacokinetic study of PZA without or with HUCHE033 (quercetin) combinations in healthy volunteers, HUCHE033 could decreased amidase activity in human, pharmacokinetic parameters of 5-OH-PA with AUC and metabolic ratio (AUC5-OH-PA/ AUCPZA and AUCPA/ AUCPZA) were significantly inhibited 25% and 39%, respectively (p < 0.01). HUCHE033 did decrease plasma level of PZA toxic metabolites, such as 5-OH-PA and PA, but did not affect PZA in human. Furthermore, an anti-TB efficacy assay revealed that above selected CYP2E1 or amidase inhibitor combinations did not affect the anti-TB effects of anti-TB drugs. In addition, we found that XO rs1884725 or rs2295475 mutant type could be a risk factor of ATDH in 411 TB patients (mutant vs. wildtype: Odds ratio [OR], 1.71, p = 0.043; mutant vs. wildtype: [OR], 4.32, p = 0.006, respectively).
Conclusions: (1) To our knowledge, this is the first report of kaempferol’s utility as an adjuvant for preventing CYP2E1-mediated hepatotoxicity induced by drugs such as INH and RIF; (2) Mannitol was an FDA-approved excipient, was identified as a CYP2E1 inhibitor that could be a useful component to eradicate the anti-TB drugs-induced hepatotoxicity; (3) This is the first report of a cell-line, animal, and clinical trial confirming that the metabolite 5-OH-PA is responsible for PZA-induced hepatotoxicity; (4) Xanthine oxidase SNP rs2295475 polymorphism could be a risk factor associated with susceptibility to ATDH.

第壹章、 緒論 .................................................................................................1
第一節、 前言 .................................................................................................1
第二節、 藥物代謝 .............................................................................................4
第三節、 結核病 ...............................................................................................6
一、 抗結核藥物及其治療 ........................................................................................7
二、 抗結核藥物及其藥物副作用之關係 .............................................................................10
三、 藥物與其相關代謝酵素抑制劑之相互關係 ........................................................................13
第四節、 抗結核藥物代謝酵素基因多型性與藥物肝毒性之相關性 ..........................................................16
第五節、 半乳糖單點法 (Galactose Single Pint, GSP).............................................................20
第貳章、 材料、實驗設計與方法 ..................................................................................23
第一節、 藥品與試劑 ...........................................................................................23
第二節、 儀器 ................................................................................................24
一、 一般儀器 ................................................................................................24
二、 高效能液相層析儀(HPLC) ...................................................................................25
三、 高效能液相層析串聯式質譜儀(LC-MS/MS) ......................................................................25
第三節、 實驗動物、細胞株與菌株 ................................................................................26
第四節、 實驗設計與方法 .......................................................................................26
一、 半乳糖單點法 (Galctose Single Point, GSP)於小鼠動物模式建立 ................................................26
1.1 試驗動物分組 .............................................................................................26
1.2 試驗處理 .................................................................................................27
二、 蛋白質含量測定 ...........................................................................................28
三、 細胞色素P450 2E1 (CYP2E1) 抑制劑之篩選 - 鼠肝微粒體與人肝微粒體 ..............................................29
3.1 肝臟微粒體製備 ............................................................................................29
3.2 實驗原理及試劑 ............................................................................................30
3.3 細胞色素P450 2E1 (CYP2E1)抑制劑的篩選 ......................................................................31
四、抑制抗結核藥物代謝酵素CYP2E1改善藥物肝毒性之研究 ..............................................................32
4.1 抗結核病藥物肝毒性動物模式建立暨CYP2E1抑制劑改善肝毒性藥效試驗 .................................................32
4.1-1 INH肝毒性模式建立暨CYP2E1抑制劑改善INH肝毒性小鼠藥效試驗 ....................................................32
4.1-2 INH/RIF肝毒性模式建立暨CYP2E1抑制劑改善INH/RIF肝毒性小鼠藥效試驗 ............................................33
4.1-3 INH/RIF/PZA肝毒性模式建立暨CYP2E1抑制劑改善INH/RIF/PZA肝毒性小鼠藥效試驗 ....................................33
4.2 CYP2E1抑制劑於改善抗結核藥物誘發肝毒性小鼠之體內藥動學試驗 .....................................................34
4.2-1 CYP2E1抑制劑於改善INH/RIF肝毒性小鼠對抗結核藥物之藥動學影響 .................................................34
4.2-2 抗結核藥物以及代謝物於液相層析串聯質譜儀 (LC-MS/MS)分析 .....................................................35
4.2-3 CYP2E1抑制劑HCHE010、HUEXC030於改善INH/RIF肝毒性小鼠對體內CYP2E1酵素之影響 .................................35
4.3 INH/RIF不併用或併用CYP2E1抑制劑HUCHE010、HUEXC030之抗菌試驗 .................................................38
4.4 低副作用抗結核二合一複方製劑Rifamate®於健康受試者之藥動學試驗 ..................................................39
4.4-1 Rifamate®不併服或併服抑制劑HUEXC030於健康受試者體內抗結核藥物之藥動學試驗 ....................................39
4.4-2 Rifamate®不併服或併服抑制劑HU030於健康受試者體內對CYP2E1酵素之影響 ..........................................40
五、 PZA肝毒性作用機轉探討及改善之研究 ..........................................................................40
5.1 PZA肝毒性機轉與改善之研究 .................................................................................40
5.1-1 製備PZA相關代謝物 ......................................................................................41
5.1-2 PZA及其代謝物於HepG2肝癌細胞毒性試驗 .....................................................................41
5.1-3 PZA及代謝物PA肝毒性大鼠模式建立暨amidase抑制劑BNPP改善PZA、PA 肝毒性大鼠藥效試驗 .............................42
5.1-4臨床患者尿液檢品與PZA肝毒性相關性分析 ......................................................................42
5.2 PZA不併服或併服amidase抑制劑HUCHE033於大鼠體內藥效藥動學試驗 .................................................43
5.3 PZA不併用或併用amidase抑制劑HUCHE033之抗菌試驗 .............................................................43
5.4 PZA不併服或併服amidase抑制劑HUCHE033於健康受試者體內之藥動學試驗 .............................................44
六、 結核病患xanthine oxidase對偶基因多型性與抗結核藥物肝毒性之風險評估............................................45
第參章、 實驗結果 ............................................................................................46
第一節、 半乳糖單點法(Galctose Single Point, GSP於小鼠動物模式建立 ..............................................46
第二節、 蛋白質測定 ...........................................................................................47
一、 鼠肝微粒體酵素懸浮液的蛋白質含量測定 ........................................................................47
二、 人肝微粒體酵素懸浮液的蛋白質含量測定 ........................................................................47
第三節、 細胞色素P450 2E1(CYP2E1)抑制劑之體外篩選 ...............................................................48
一、 鼠肝微粒體細胞色素P450 2E1抑制劑篩選結果 ...................................................................48
二、 人肝微粒體細胞色素P450 2E1抑制劑篩選結果 ...................................................................49
第四節、 低副作用抗結核病複方製劑之研究 ..........................................................................51
4.1 抗結核病藥物肝毒性動物模式建立暨CYP2E1抑制劑改善小鼠肝毒性藥效試驗 .............................................51
4.1-1 INH不併服或併服CYP2E1抑制劑於改善小鼠INH 肝毒性藥效試驗結果 ................................................51
4.1-2 INH/RIF不併服或併服CYP2E1抑制劑於改善小鼠INH/RIF肝毒性藥效試驗結果 ........................................52
4.1-3 INH/RIF/PZA不併服或併服CYP2E1抑制劑於改善小鼠INH/RIF/PZA肝毒性藥效試驗結果 .................................55
4.2 CYP2E1抑制劑於改善抗結核藥物造成肝損傷小鼠體內藥動學試驗 .....................................................55
4.2-1 INH/RIF不併服或併服CYP2E1抑制劑HUCHE010於小鼠體內藥動學試驗結果 ...........................................55
4.2-2 INH/RIF不併服或併服CYP2E1抑制劑HUEXC030於小鼠體內藥動學試驗結果 ...........................................56
4.3 INH/RIF不併用或併用CYP2E1抑制劑HUCHE010、HUEXC030之抗菌試驗結果 ............................................56
4.4 低副作用抗結核病二合一複方製劑Rifamate®於健康受試者之藥動學試驗結果 ...........................................57
第五節、 PZA肝毒性作用機轉探討及改善之研究 ......................................................................58
5.1 抗結核病藥物PZA肝毒性機轉與改善之研究 .......................................................................58
5.1-1 PZA及其代謝物於HepG2細胞毒性試驗結果 .....................................................................58
5.1-2 PZA及代謝物PA不併服或併服amidase抑制劑改善大鼠體內PZA、PA肝毒性藥效試驗結果 ..................................58
5.1-3 TB臨床病患尿液檢品與肝毒性相關性分析結果 ...................................................................59
5.2 PZA不併服或併服amidase抑制劑HUCHE033於大鼠體內藥動學試驗結果 .................................................60
5.3 PZA不併用或併用amidase抑制劑HUCHE033之抗菌試驗結果 ..........................................................60
5.4 PZA不併服或併服amidase抑制劑HUCHE033於健康受試者體內藥動學試驗結果 ............................................61
第六節、 臨床結核病患xanthine oxidase對偶基因多型性與抗結核藥物肝毒性之風險評估 .....................................62
第肆章、 討論 .................................................................................................64
第伍章、 結論 .................................................................................................72
第陸章、 參考文獻 .............................................................................................73
第柒章、 附表 .................................................................................................87
附圖 ................................................................................................139
SCI 發表文章.........................................................................................164

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