肝损状态下尿苷二磷酸葡萄糖醛酸转移酶研究进展

中国临床药理学与治疗学 ›› 2009, Vol. 14 ›› Issue (12): 1321-1328.

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肝损状态下尿苷二磷酸葡萄糖醛酸转移酶研究进展

姜杉, 郝海平, 王广基

中国药科大学药代动力学重点实验室, 南京 210009, 江苏

收稿日期:2009-10-12 修回日期:2009-11-13 发布日期:2020-10-20
通讯作者: 王广基, 男, 博士, 教授, 博士研究生导师, 研究方向:药物代谢动力学。Tel:13951774279 E-mail:hhp770505@yahoo.com.cn
作者简介:姜杉, 男, 硕士研究生, 研究方向:药物代谢动力学。Tel:15850601631 E-mail:jiangshan oov@163 .com；王广基, 博士、教授、博士生导师, 中国药科大学副校长。1953 年生, 1977 年9月毕业于中国药科大学, 毕业后留校任教。1982 年11 月至1984 年9 月赴英国剑桥及瑞典卡罗琳斯卡医学院学习药物代谢动力学, 回国后任讲师。1990 年4 月至91 年4 月, 在澳大利亚昆士兰大学药学系, 攻读博士学位, 主攻方向药物代谢动力学。1991 年4 月至93 年7 月, 在新西兰Otago 大学药学院, 攻读博士学位, 主攻方向眼用制剂吸收动力学。1993 年8 月至95 年10 月, 在新西兰Otago 大学药学院, 进行博士后研究, 95 年10 月回国。现任中国药科大学副校长, 科技部临床前药物代谢动力学研究平台主任(全国牵头人), 江苏省药物代谢动力学重点实验室主任, 中国药学会应用药理专业委员会主任委员, 中国药理学会药物代谢动力学专业委员会副主任委员, 中国药理学会制药工业专业委员会副主任委员, 江苏省药理学会常务理事兼副秘书长, 国家药品食品监督管理局和江苏省药品审评专家,国家自然科学基金委评审委员, 国家人事部顾问委员会委员,《中国药理学报》,《亚洲药物代谢动力学杂志》, 《中国药科大学学报》, 《中国临床药理学与治疗学》, 《亚洲临床药理学与治疗学》等核心学术期刊杂志编委等职, 享受国务院特殊津贴。
基金资助:
国家自然科学基金(30801422); 国家“ 十一五” 重大新药创制专项“ 临床前药物代谢动力学技术平台”(2009ZX09304-001)资助;

Hepatic UDP-glucuronosyltransferases in liver injury

JIANG Shan, HAO Hai-ping, WANG Guang-ji

Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009,Jiangsu, China

Received:2009-10-12 Revised:2009-11-13 Published:2020-10-20

摘要/Abstract

摘要： 肝脏是人体内最重要的代谢器官, 包含绝大部分的Ⅰ 相和Ⅱ相代谢酶, 在内源性和外源性物质的代谢解毒方面起着重要的作用。参与葡萄糖醛酸代谢的尿苷二磷酸葡萄糖醛酸转移酶(UGT)是Ⅱ 相代谢中最重要的酶, 与常见的CYP450 酶相比, 研究相对滞后, 尤其在肝损伤状态下UGT 的相关研究仍处于探索阶段。本文参考最新UGT 的研究成果, 综述了UGT 分子生物学目前研究的概况、肝脏分布及其与肝脏疾病的关系;总结了几种不同诱因的肝损伤病理状态UGT表达和葡萄糖醛酸代谢的变化情况并且深入探讨了相关机制, 旨在为药物的肝脏代谢尤其是在肝损状态下葡萄糖醛酸结合消除研究提供一定的参考依据, 为肝脏疾病患者的临床合理用药提供指导。

关键词: 肝脏, 葡萄糖醛酸转移酶, Ⅱ相代谢;, 肝损伤

Abstract: Liver is the most important metabolic organ in human, including the vast majority of metabolic enzymes involving phase Ⅰ and phase Ⅱ and playing an important role on detoxification of many endogenous and exogenous substances.UDP-glucuronosyltransferases (UGT)is the most important phase Ⅱ metabolic enzyme that catalize glucuronidation in human, as compared with the CYP450 enzymes, study of UGTs lags behind, especially, the state of UGTs in liver injury is still poorly understood.This review summarizes latest studies of the UGTs in gene, protein structure and function, distribution in liver and relationship with the liver disease, then we discuss the effects of several common liver injury on hepatic UGT and glucuronidation.It will provide more reliable reference in durg metabolism in liver injury and guide the clinical rational use of drugs.

Key words: liver, UDP-glucuronosyltransferases, phase Ⅱ metabolism;, liver injury

中图分类号:

R969.1

姜杉, 郝海平, 王广基. 肝损状态下尿苷二磷酸葡萄糖醛酸转移酶研究进展[J]. 中国临床药理学与治疗学, 2009, 14(12): 1321-1328.

JIANG Shan, HAO Hai-ping, WANG Guang-ji. Hepatic UDP-glucuronosyltransferases in liver injury[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2009, 14(12): 1321-1328.

参考文献

[1] Nagar S, Remmel RP.Uridine diphosphoglucuronosyltransferase pharmacogenetics and cancer[J]. Oncogene, 2006, 25(11):1659-1672.
[2] FinelM, Kurkela M.The UDP-glucuronosyltransferases as oligomeric enzymes[J].2008, 9(1):70-76.
[3] Bock KW, Kö hle C.Topological aspects of oligomeric UDP-glucuronosyltransferases in endoplasmic reticulum membranes:Advances and open questions[J].Biochem pharmacol, 2009, 77(9):1458-1465.
[4] Nakamura A, Nakajima M, Yamanaka H, et al.Expression of UGT1A and UGT2B mRNA in Human Normal Tissues and Various Cell Lines[J].Drug Metab Dispos, 2008, 36(8):1461-1464.
[5] Hoyumpa AM, Schenker S.Is glucuronidation truly preserved in patients with liver disease[J] ? Hepatology, 1991, 13(4):786-795.
[6] Knapp SA, Green MD, Tephly TR, et al.Immunohistochemical demonstration of isozyme-and strain specific differences in the intralobular Iocalizations and distributions of UDP-glucuronosyltransferases in livers of untreated rats[J].Mol Pharmacol, 1988, 33(1):14-21.
[7] Debinski HS, Lee CS, Danks JA, et al.Localization of uridine 5'-diphosphate-glucuronosyltransferase in human liver injury[J].Gastroenterology, 1995, 108(5):1464-1469.
[8] Kardon T, Coffey MJ, Bánhegyi G, et al.Transcriptional induction of bilirubin UDP-glucuronosyltransrase by ethanol in rat liver[J].Alcohol, 2000, 21(3):251-257.
[9] Li Y, Wang K, Yu T, et al.The expression of uridine diphosphate glucuronosyltransferase mRNA regulated by alcohol[J].Zhonghua Gan Zang Bing Za Zhi, 2001, 9(3):172-174.
[10] Bichlmaier I, KurkelaM, Joshi T, et al.Isoform-selective inhibition of the human UDP-glucuronosyltransferase 2B7 by isolongifolol derivatives[J].J Med Chem, 2007, 50(11):2655-2664.
[11] Soars MG, Petullo DM, Eckstein JA, et al.Wrighton An assessment of udp-glucuronosyltransferase induction using primary human hepatocytes[J].Drug Metab Dispos, 2004, 32(1):140-148.
[12] Catania VA, Luquita MG, Sánchez Pozzi EJ, et al.Effect of spironolactone on the expression of rat hepatic UDP-glucuronosyltransferase[J].Biochem Pharmacol, 2003, 66(1):171-177.
[13] Jeong H, Choi S, Song JW, et al.Regulation of UDPglucuronosyltransferase (UGT) 1A1 by progesterone and its impact on labetalol elimination[J].Xenobiotica, 2008, 38(1):62-75.
[14] Buckley DB, Klaassen CD.Mechanism of gender-divergent UDP-glucuronosy ltransferase mRNA expression in mouse liver and kidney[J].Drug Metab Dispos, 2009, 37(4):834-840.
[15] Usui T, Kuno T, Mizutani T.Induction of human UDPglucuronosyltransferase 1A1 by cortisol-GR[J].Mol Biol Rep, 2006, 33(2):91-96.
[16] Kostrubsky SE, Sinclair JF, Strom SC, et al.Phenobarbital and phenytoin increased acetaminophen hepatotoxicity due to inhibition of UDP-glucuronosy ltransferases in cultured human hepatocytes[J].Toxicol Sci, 2005, 87(1): 146-155.
[17] Huang YY, Huang MJ, Yang SS, et al.Variations in the UDP-glucuronosyltransferase 1A1 gene for the development of unconjugated hyperbilirubinemia in Taiwanese[J]. Pharmacogenomics, 2008, 9(9):1229-1235.
[18] Philipp T, Durazzo M, Trautwein C, et al.Recognition of uridine diphosphate glucuronosyl transferases by LKM-3 antibodies in chronic hepatitis D[J].Lancet, 1994, 344(8922):578-581.
[19] Howden CW, Birnie GG, Brodie MJ.Drug metabolism in liver disease[J].Pharmacol Ther, 1989, 40(3):439-479.
[20] Ochs HR, Greenblatt DJ, Verburg-Ochs B, et al.Temazepam clearance unaltered in cirrhosis[J].Am J Gastroenterol, 1986, 81(1):80-84.
[21] Patwardhan RV, Johnson RF, Hoyumpa AM, et al.Normal metabolism of morphine in cirrhosis[J].Gastroenterology, 1981, 81(6):1006-1011.
[22] Crotty B, Watson KJR, Desmond PV, et al.Hepatic extraction of morphine is impaired in cirrhosis[J].Eur J Clin Pharmacol, 1989, 36(5):501-506.
[23] Gerkens JF, Desmond PV, Schenker S, et al.Hepatic and extrahepatic glucuronidation of lorazepam in the dog[J].Hepatology, 1981, 1(4):329-335.
[24] Richardson TA, Sherman M, Kalman D, et al.Expression of UDP-Glucuronosyltransferase isoform mRNAs during inflammation and infection in mouse liver and kidney[J]. Drug Metab Dispos, 2006, 34(3):351-353.
[25] CongiuM, MashfordML, Slavin JL, et al.UDP glucuronosyltransferase mRNA levels in human liver disease[J]. Drug Metab Dispos, 2002, 30(2):129-134.
[26] Monshouwer M, Witkamp RF.Cytochromes and cytokines:changes in drug disposition in animals during an acute phase response:a mini-review[J].Vet Q, 2000, 22(1):17-20.
[27] Richardson TA, Morgan ET.Hepatic cytochrome P450 gene regulation during endotoxin-induced inflammation in nuclear receptor knockout mice[J].J Pharmacol Exp Ther, 2005, 314(2):703-709.
[28] Richardson TA, ShermanM, Antonovic L, et al.Hepatic and renal cytochrome P450 gene regulation during Citrobacter rodentium infection in wild-type and toll-like receptor 4 mutant mice[J].Drug Metab Dispos, 2006, 34(3):354-360.
[29] Monshouwer M, Witkamp RF, Nujmeijer SM, et al.Suppression of cytochrome P450- and UDP glucuronosyl transferase- dependent enzyme activities by proinflammatory cytokines and possible role of nitric oxide in primary cultures of pig hepatocytes[J].Toxicol Appl Pharmacol, 1996, 137(2):237-244.
[30] Strasser SI, Mashford ML, Desmond PV.Regulation of uridine diphosphate glucuronosy ltransferase during the acute-phase response[J].J Gastroenterol Hepatol, 1998, 13(1):88-94.
[31] Wyles DL, Gerber JG.Antiretroviral drug pharmacokinetics in hepatitis with hepatic dysfunction[J].Clin Infect Dis, 2005, 40(1):174-181.
[32] Furlan V, Demirdjian S, Bourdon O, et al.Glucuronidation of drugs by hepatic microsomes derived from healthy and cirrhotic human livers[J].J Pharmacol Exp Ther, 1999, 289(2):1169-1175.
[33] Debinski HS, Mackenzie PI, Lee CS, et al.UDP glucuronosyltransferase in the cirrhotic rat liver[J].J Gastroenterol Hepatol, 1996, 11(4):373-379.
[34] Buckley DB, Klaassen CD.Induction of mouse UDP-glucuronosyltransferase mRNA expression in liver and intestine by activators of aryl-hydrocarbon receptor, constitutive androstane receptor, pregnane X receptor, peroxisome proliferator-activated receptor alpha, and nuclear factor erythroid 2-related factor 2[J].Drug Metab Dispos, 2009, 37(4):847-856.
[35] Shelby MK, Klaassen CD.Induction of rat UDP-glucuronosy ltransferases in liver and duodenum by microsomal enzyme inducers that activate various transcriptional pathways[J].Drug Metab Dispos, 2006, 34(10):1772-1778.
[36] Osabe M, Sugatani J, Fukuyama T, et al.Expression of hepatic UDP-glucuronosyltransferase 1A1 and 1A6 correlated with increased expression of the nuclear constitutive androstane receptor and peroxisome proliferator -activated receptor αin male rats fed a high-fat and high -sucrose diet[J].Drug Metab Dispos, 2008, 36(2):294-302.
[37] Senekeo-Effenberger K, Chen S, Brace-Sinnokrak E, et al.Expression of the Human UGT1 Locus in Transgenic Mice by 4-Chloro-6-(2, 3-xylidino)-2-pyrimidinylthioacetic Acid (WY-14643)and Implications on Drug Metabolism through Peroxisome Proliferator-Activated Receptor αActivation[J].Drug Metab Dispos, 2007, 35(3):419-427.
[38] Gardner-Stephen DA, Mackenzie PI.Liver-enriched transcription factors and their role in regulating UDP glucuronosy ltransferase gene expression[J].Curr Drug Metab, 2008, 9(5):439-452.
[39] 张利, 周宏灏.孤儿核受体对尿苷二磷酸葡萄糖醛酸转移酶基因转录调节的研究进展[J].中国临床药理学与治疗学, 2007, 12(9):974-979.
[40] Witassek F, Bircher J, Huguenin P, et al.Abnormal glucuronidation of zomepirac in patients with cirrhosis of the liver[J].Hepatology, 1983, 3(3):415-422.
[41] Forrest JA, Adrienssens P, Finlay son ND, et al.Paracetamol metabolism in chronic liver disease[J].Eur J Clin Pharmacol, 1979, 15(6):427-431.
[42] Hasselstrom J, Erikson S, Persson A, et al.The metabolism and bioavailability of morphine in patients with severe liver cirrhosis[J].Br J Clin Pharmacol, 1990, 29(3):289-297.
[43] Kundu R, Dasgupta S, Biswas A, et al.Cajanus cajan Linn.(Leguminosae) prevents alcohol-induced rat liver damage and augments cytoprotective function[J].J Ethnopharmacol, 2008, 118(3):440-447.
[44] Villanueva SS, RuizML, Ghanem CI, et al.Hepatic synthesis and urinary elimination of acetaminophen glucuronide are exacerbated in bile duct-ligated rats[J].Drug Metab Dispos, 2008, 36(3):475-480.
[45] Hasegawa Y, Kishimoto S, Takahashi H, et al.Altered expression of MRP2, MRP3 and UGT2B1 in the liver affects the disposition of morphine and its glucuronide conjugate in a rat model of cholestasis[J].J Pharm Pharmacol, 2009, 61(9):1205-1210.

肝损状态下尿苷二磷酸葡萄糖醛酸转移酶研究进展

Hepatic UDP-glucuronosyltransferases in liver injury

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