HepaRG细胞在药物代谢相关研究中的应用进展
|
摘要
HepaRG细胞在二甲亚砜存在下可分化为肝样细胞和胆管样细胞,分化阶段表达肝特异性功能包括CYP酶、转运蛋白及核受体,是替代原代人肝细胞研究体外药物代谢的合适模型,对药物开发及预测临床药物相互作用具有重要的意义。目前HepaRG细胞主要用于药物代谢机制、药物相互作用、药物肝毒性、细胞毒性和遗传毒性研究等。该文综述了近年来HepaRG细胞在药物代谢相关研究中的应用。
引文
[1]宋复兴,王蓉,原永芳.药物代谢细胞色素P450酶学与研究方法应用进展[J].医学综述,2017,23(4):665-669.
[2]薛正楷,魏泓.重组肝CYP3A4与CYP2C29细胞微粒体药物代谢动力学比较[J].医药导报,2015,34(1):15-20.
[3]ANDERSSON T B,KANEBRATT K P,KENNA J G.The HepaRG cell line:a unique in vitro tool for understanding drug metabolism and toxicology in human[J].Expert Opin Drug Metab Toxicol,2012,8(7):909-910.
[4]方飞,吴新荣,罗明俐,等.Hep G2细胞胰岛素抵抗模型的建立及在筛选桑叶有效部位中的应用[J].医药导报,2012,31(6):691-694.
[5]张志敏,秦传蓉,章必成,等.小檗碱对肝癌Hep G2细胞增殖和凋亡的调节作用[J].医药导报,2018,37(5):512-517.
[6]GODOY P,HEWITT N J,ALBRECHT U,et al.Recent advances in 2D and 3D in vitro systems using primary hepatocytes,alternative hepatocyte sources and nonparenchymal liver cells and their use in investigating mechanisms of hepatotoxicity,cell signaling and ADME[J].Arch Toxicol,2013,87(8):1315-1530.
[7]GRIPON P,RUMIN S,URBAN S,et al.Infection of a human hepatoma cell line by hepatitis B virus[J].Proc Natl Acad Sci USA,2002,99(24):15655-15660.
[8]蒋黎,王宇明.HepaRG细胞的生物学特点及其应用[J].肝脏,2010,15(5):380-382.
[9]JACKSON J P,LI L,CHAMBERLAIN E D,et al.Contextualizing hepatocyte functionality of cryopreserved HepaRGcell cultures[J].Drug Metab Dispos,2016,44(9):1463-1479.
[10]KAMALIAN L,DOUGLAS O,JOLLY C E,et al.The utility of HepaRG cells for bioenergetic investigation and detection of drug-induced mitochondrial toxicity[J].Toxicol In Vitro,2018,53:136-147.
[11]YOKOYAMA Y,SASAKI Y,TERASAKI N,et al.Comparison of drug metabolism and its related hepatotoxic effects in HepaRG,cryopreserved human hepatocytes,and Hep G2 cell cultures[J].Biol Pharm Bull,2018,41(5):722-732.
[12]NELSONL J,MORGAN K,TRESKES P,et al.Human hepatic HepaRG cells maintain an organotypic phenotype with high intrinsic CYP450 activity/metabolism and significantly outperform standard Hep G2/C3A cells for pharmaceutical and therapeutic applications[J].Basic Clin Pharmacol Toxicol,2017,120(1):30-37.
[13]WU Y,GENG X C,WANG J F,et al.The HepaRG cell line,a superior in vitro model to L-02,Hep G2 and hi Heps cell lines for assessing drug-induced liver injury[J].Cell Biol Toxicol,2016,32(1):37-59.
[14]ABE K,BRIDGES A S,BROUWER K L.Use of sandwichcultured human hepatocytes to predict biliary clearance of angiotensinⅡreceptor blockers and HMG-CoA reductase inhibitors[J].Drug Metab Dispos,2009,37(3):447-452.
[15]MALINEN M M,KANNINEN L K,CORLU A,et al.Differentiation of liver progenitor cell line to functional organotypic cultures in 3D nanofibrillar cellulose and hyaluronan-gelatin hydrogels[J].Biomaterials,2014,35(19):5110-5121.
[16]WANG Z,LUO X,ANENE-NZELU C,et al.HepaRGculture in tethered spheroids as an in vitro threedimensional model for drug safety screening[J].J Appl Toxicol,2014,35(8):909-917.
[17]LEITE S B,WILK-ZASADNA I,ZALDIVAR J M,et al.Three-dimensional HepaRG model as an attractive tool for toxicity testing[J].Toxicol Sci,2012,130(1):106-116.
[18]REBELO S P,COSTA R,ESTRADA M,et al.HepaRGmicroencapsulated spheroids in DMSO free culture:novel culturing approaches for enhanced xenobiotic and biosynthetic metabolism[J].Arch Toxicol,2015,89(8):1347-1358.
[19]STAMPELLA A,RIZZITELLI G,DONATI F,et al.Human hepatoma cell lines on gas foaming templated alginate scaffolds for in vitro drug-drug interaction and metabolism studies[J].Toxicology In Vitro,2015,30(1):331-340.
[20]ANTHRIEU S,CHESNC,LI R,et al.Stable expression,activity,and inducibility of cytochromes P450in differentiated HepaRG cells[J].Drug Metab Dispos,2010,38(3):516-525.
[21]LüBBERSTEDT M,MüLLER-VIEIRA U,MAYER M,et al.HepaRG human hepatic cell line utility as a surrogate for primary human hepatocytes in drug metabolism assessment in vitro[J].J Pharm Toxic Meth,2011,63(1):59-68.
[22]MADEC S,CEREC V,PLéE-GAUTIER E,et al.CYP4F3Bexpression is associated with differentiation of HepaRGhuman hepatocytes and unaffected by fatty acid overload[J].Drug Metab Dispos,2011,39(10):1987-1996.
[23]ANINAT C,PITON A,GLAISE D,et al.Expression of cytochromes P_(450),conjugating enzymes and nuclear receptors in human hepatoma HepaRG cells[J].Drug Metab Dispos,2006,34(1):75-83.
[24]CASABAR R C,DAS P C,DEKREY G K,et al.Endosulfan induces CYP2B6 and CYP3A4 by activating the pregnane X receptor[J].Toxicol Appl Pharmacol,2010,245(3):335-343.
[25]KüBLBECK J,LAITINEN T,JYRKK?RINNE J,et al.Use of comprehensive screening methods to detect selective human CAR activators[J].Biochem Pharmacol,2011,82(12):1994-2007.
[26]CASABAR R C,WALLACE A D,HODGSON E,et al.Metabolism of endosulfan-alpha by human liver microsomes and its utility as a simultaneous in vitro probe for CYP2B6and CYP3A4[J].Drug Metab Dispos,2006,34(10):1779-1785.
[27]SAVARY C C,JOSSéR,BRUYèRE A,et al.Interactions of endosulfan and methoxychlor involving CYP3A4 and CYP2B6 in human HepaRG cells[J].Drug Metab Dispos,2014,42(8):1235-1240.
[28]BERGER B,BACHMANN F,DUTHALER U,et al.Cytochrome P450 enzymes involved in metoprolol metabolism and use of metoprolol as a CYP2D6phenotyping probe drug[J].Front Pharmacol,2018,9:774.
[29]KITTLER K,FESSARD V,MAUL R,et al.CYP3A4activity reduces the cytotoxic effects of okadaic acid in HepaRG cells[J].Arch Toxicol,2014,88(8):1519-1526.
[30]FERREIRA A,RODRIGUES M,SILVESTRE S,et al.HepaRG cell line as an in vitro model for screening drugdrug interactions mediated by metabolic induction:amiodarone used as a model substance[J].Toxicol In Vitro,2014,28(8):1531-1535.
[31]HOWARD-THOMPSON A,HURDLE A C,ARNOLD L B,et al.Intracerebral hemorrhage secondary to a warfarinmetronidazole interaction[J].Am J Geriatr Pharmacother,2008,6(1):33-36.
[32]LANE M A,ZERINGUE A,MCDONALD J R.Serious bleeding events due to warfarin and antibiotic coprescription in a cohort of veterans[J].Am J Med,2014,127(7):657-663.
[33]KUDO T,ENDO Y,TAGUCHI R,et al.Metronidazole reduces the expression of cytochrome P450enzymes in HepaRGcells and cryopreserved human hepatocytes[J].Xenobiotica,2015,45(5):413-419.
[34]OGASAWARA A,KATO N,TORIMOTO N,et al.Cytochrome P4501A2 messenger RNA is a more reliable marker than cytochrome P4501A2 activity,phenacetin O-Deethylation,for assessment of induction potential of drugmetabolizing enzymes using HepaRG cells[J].Drug Metab Lett,2018,12(1):14-23.
[35]ZHANG Y W,ZHENGX W,LIU Y J,et al.Effect of oridonin on cytochrome P450expression and activities in HepaRG cell[J].Pharmacology,2018,101(5/6):246-254.
[36]KIM J,LEE Y J,KIM Y A,et al.Aqueous extract of phragmitis rhizoma ameliorates myelotoxicity of docetaxel in vitro and in vivo[J].BMC Complement Altern Med,2017,17(1):393.
[37]MCGILL M R,YAN H M,RAMACHANDRAN A,et al.HepaRG cells:a human model to study mechaisms of acetaminophen hepatotoxicity[J].Hepatology,2011,53(3):974-982.
[38]CHAN J C Y,SOH A C K,KIOH D Y Q,et al.Reactive metabolite-induced protein glutathionylation:a potentially novel mechanism underlying acetaminophen hepatotoxicity[J].Mol Cell Proteomics,2018,17(10):2034-2050.
[39]KNEBEL C,HEISE T,ZANGER U M,et al.The azole fungicide tebuconazole affects human CYP1A1 and CYP1A2 expression by an aryl hydrocarbon receptordependent pathway[J].Food Chem Toxicol,2019,123:481-491.
[40]FAHRNER R,MLLER A,PRESS A T,et al.Short-term treatment with taurolidine is associated with liver injury[J].BMC Pharmacol Toxicol,2017,18(1):61.
[41]DONGA X,FU J,YIN X,et al.Induction of apoptosis in HepaRG cell line by aloe-emodin through generation of reactive oxygen species and the mitochondrial pathway[J].Cell Physiol Biochem,2017,42(2):685-696.
[42]FERRON P J,HOGEVEEN K,DE SOUSA G,et al.Modulation of CYP3A4 activity alters the cytotoxicity of lipophilic phycotoxins in human hepatic HepaRG cells[J].Toxicol In Vitro,2016,33:136-146.
[43]BURBAN A,SHARANEK A,GUGUEN-GUILLOUZO C,et al.Endoplasmic reticulum stress precedes oxidative stress in antibiotic-induced cholestasis and cytotoxicity in human hepatocytes[J].Free Radic Biol Med,2018,115:166-178.
[44]BURBANK M G,SHARANEK A,BURBAN A,et al.Mechanistic Insights in cytotoxic and cholestatic potential of the endothelial receptor antagonists using HepaRG cells[J].Toxicol Sci,2017,157(2):451-464.
[45]SHARANEK A,BURBAN A,HUMBERT L,et al.Progressive and preferential cellular accumulation of hydrophobic bile acids induced by cholestatic drugs is associated with inhibition of their amidation and sulfation[J].Drug Metab Dispos,2017,45(12):1292-1303.
[46]TOMIDA T,ISHIMURA M,IWAKI M.A cell-based assay using HepaRG cells for predicting drug-induced phospholipidosis[J].Toxicol Sci,2017,42(5):641-650.
[47]PANT A,RONDINI E A,KOCAREK T A.Farnesol induces fatty acid oxidation and decreases triglyceride accumulation in steatotic HepaRG cells[J].Toxicol Appl Pharmacol,2019,365(15):61-70.
[48]GAO X,LIU Y.A transcriptomic study suggesting human i PSC-derived hepatocytes potentially offer a better in vitro model of hepatotoxicity than most hepatoma cell lines[J].Cell Biol Toxicol,2017,33(4):407-421.
[2]薛正楷,魏泓.重组肝CYP3A4与CYP2C29细胞微粒体药物代谢动力学比较[J].医药导报,2015,34(1):15-20.
[3]ANDERSSON T B,KANEBRATT K P,KENNA J G.The HepaRG cell line:a unique in vitro tool for understanding drug metabolism and toxicology in human[J].Expert Opin Drug Metab Toxicol,2012,8(7):909-910.
[4]方飞,吴新荣,罗明俐,等.Hep G2细胞胰岛素抵抗模型的建立及在筛选桑叶有效部位中的应用[J].医药导报,2012,31(6):691-694.
[5]张志敏,秦传蓉,章必成,等.小檗碱对肝癌Hep G2细胞增殖和凋亡的调节作用[J].医药导报,2018,37(5):512-517.
[6]GODOY P,HEWITT N J,ALBRECHT U,et al.Recent advances in 2D and 3D in vitro systems using primary hepatocytes,alternative hepatocyte sources and nonparenchymal liver cells and their use in investigating mechanisms of hepatotoxicity,cell signaling and ADME[J].Arch Toxicol,2013,87(8):1315-1530.
[7]GRIPON P,RUMIN S,URBAN S,et al.Infection of a human hepatoma cell line by hepatitis B virus[J].Proc Natl Acad Sci USA,2002,99(24):15655-15660.
[8]蒋黎,王宇明.HepaRG细胞的生物学特点及其应用[J].肝脏,2010,15(5):380-382.
[9]JACKSON J P,LI L,CHAMBERLAIN E D,et al.Contextualizing hepatocyte functionality of cryopreserved HepaRGcell cultures[J].Drug Metab Dispos,2016,44(9):1463-1479.
[10]KAMALIAN L,DOUGLAS O,JOLLY C E,et al.The utility of HepaRG cells for bioenergetic investigation and detection of drug-induced mitochondrial toxicity[J].Toxicol In Vitro,2018,53:136-147.
[11]YOKOYAMA Y,SASAKI Y,TERASAKI N,et al.Comparison of drug metabolism and its related hepatotoxic effects in HepaRG,cryopreserved human hepatocytes,and Hep G2 cell cultures[J].Biol Pharm Bull,2018,41(5):722-732.
[12]NELSONL J,MORGAN K,TRESKES P,et al.Human hepatic HepaRG cells maintain an organotypic phenotype with high intrinsic CYP450 activity/metabolism and significantly outperform standard Hep G2/C3A cells for pharmaceutical and therapeutic applications[J].Basic Clin Pharmacol Toxicol,2017,120(1):30-37.
[13]WU Y,GENG X C,WANG J F,et al.The HepaRG cell line,a superior in vitro model to L-02,Hep G2 and hi Heps cell lines for assessing drug-induced liver injury[J].Cell Biol Toxicol,2016,32(1):37-59.
[14]ABE K,BRIDGES A S,BROUWER K L.Use of sandwichcultured human hepatocytes to predict biliary clearance of angiotensinⅡreceptor blockers and HMG-CoA reductase inhibitors[J].Drug Metab Dispos,2009,37(3):447-452.
[15]MALINEN M M,KANNINEN L K,CORLU A,et al.Differentiation of liver progenitor cell line to functional organotypic cultures in 3D nanofibrillar cellulose and hyaluronan-gelatin hydrogels[J].Biomaterials,2014,35(19):5110-5121.
[16]WANG Z,LUO X,ANENE-NZELU C,et al.HepaRGculture in tethered spheroids as an in vitro threedimensional model for drug safety screening[J].J Appl Toxicol,2014,35(8):909-917.
[17]LEITE S B,WILK-ZASADNA I,ZALDIVAR J M,et al.Three-dimensional HepaRG model as an attractive tool for toxicity testing[J].Toxicol Sci,2012,130(1):106-116.
[18]REBELO S P,COSTA R,ESTRADA M,et al.HepaRGmicroencapsulated spheroids in DMSO free culture:novel culturing approaches for enhanced xenobiotic and biosynthetic metabolism[J].Arch Toxicol,2015,89(8):1347-1358.
[19]STAMPELLA A,RIZZITELLI G,DONATI F,et al.Human hepatoma cell lines on gas foaming templated alginate scaffolds for in vitro drug-drug interaction and metabolism studies[J].Toxicology In Vitro,2015,30(1):331-340.
[20]ANTHRIEU S,CHESNC,LI R,et al.Stable expression,activity,and inducibility of cytochromes P450in differentiated HepaRG cells[J].Drug Metab Dispos,2010,38(3):516-525.
[21]LüBBERSTEDT M,MüLLER-VIEIRA U,MAYER M,et al.HepaRG human hepatic cell line utility as a surrogate for primary human hepatocytes in drug metabolism assessment in vitro[J].J Pharm Toxic Meth,2011,63(1):59-68.
[22]MADEC S,CEREC V,PLéE-GAUTIER E,et al.CYP4F3Bexpression is associated with differentiation of HepaRGhuman hepatocytes and unaffected by fatty acid overload[J].Drug Metab Dispos,2011,39(10):1987-1996.
[23]ANINAT C,PITON A,GLAISE D,et al.Expression of cytochromes P_(450),conjugating enzymes and nuclear receptors in human hepatoma HepaRG cells[J].Drug Metab Dispos,2006,34(1):75-83.
[24]CASABAR R C,DAS P C,DEKREY G K,et al.Endosulfan induces CYP2B6 and CYP3A4 by activating the pregnane X receptor[J].Toxicol Appl Pharmacol,2010,245(3):335-343.
[25]KüBLBECK J,LAITINEN T,JYRKK?RINNE J,et al.Use of comprehensive screening methods to detect selective human CAR activators[J].Biochem Pharmacol,2011,82(12):1994-2007.
[26]CASABAR R C,WALLACE A D,HODGSON E,et al.Metabolism of endosulfan-alpha by human liver microsomes and its utility as a simultaneous in vitro probe for CYP2B6and CYP3A4[J].Drug Metab Dispos,2006,34(10):1779-1785.
[27]SAVARY C C,JOSSéR,BRUYèRE A,et al.Interactions of endosulfan and methoxychlor involving CYP3A4 and CYP2B6 in human HepaRG cells[J].Drug Metab Dispos,2014,42(8):1235-1240.
[28]BERGER B,BACHMANN F,DUTHALER U,et al.Cytochrome P450 enzymes involved in metoprolol metabolism and use of metoprolol as a CYP2D6phenotyping probe drug[J].Front Pharmacol,2018,9:774.
[29]KITTLER K,FESSARD V,MAUL R,et al.CYP3A4activity reduces the cytotoxic effects of okadaic acid in HepaRG cells[J].Arch Toxicol,2014,88(8):1519-1526.
[30]FERREIRA A,RODRIGUES M,SILVESTRE S,et al.HepaRG cell line as an in vitro model for screening drugdrug interactions mediated by metabolic induction:amiodarone used as a model substance[J].Toxicol In Vitro,2014,28(8):1531-1535.
[31]HOWARD-THOMPSON A,HURDLE A C,ARNOLD L B,et al.Intracerebral hemorrhage secondary to a warfarinmetronidazole interaction[J].Am J Geriatr Pharmacother,2008,6(1):33-36.
[32]LANE M A,ZERINGUE A,MCDONALD J R.Serious bleeding events due to warfarin and antibiotic coprescription in a cohort of veterans[J].Am J Med,2014,127(7):657-663.
[33]KUDO T,ENDO Y,TAGUCHI R,et al.Metronidazole reduces the expression of cytochrome P450enzymes in HepaRGcells and cryopreserved human hepatocytes[J].Xenobiotica,2015,45(5):413-419.
[34]OGASAWARA A,KATO N,TORIMOTO N,et al.Cytochrome P4501A2 messenger RNA is a more reliable marker than cytochrome P4501A2 activity,phenacetin O-Deethylation,for assessment of induction potential of drugmetabolizing enzymes using HepaRG cells[J].Drug Metab Lett,2018,12(1):14-23.
[35]ZHANG Y W,ZHENGX W,LIU Y J,et al.Effect of oridonin on cytochrome P450expression and activities in HepaRG cell[J].Pharmacology,2018,101(5/6):246-254.
[36]KIM J,LEE Y J,KIM Y A,et al.Aqueous extract of phragmitis rhizoma ameliorates myelotoxicity of docetaxel in vitro and in vivo[J].BMC Complement Altern Med,2017,17(1):393.
[37]MCGILL M R,YAN H M,RAMACHANDRAN A,et al.HepaRG cells:a human model to study mechaisms of acetaminophen hepatotoxicity[J].Hepatology,2011,53(3):974-982.
[38]CHAN J C Y,SOH A C K,KIOH D Y Q,et al.Reactive metabolite-induced protein glutathionylation:a potentially novel mechanism underlying acetaminophen hepatotoxicity[J].Mol Cell Proteomics,2018,17(10):2034-2050.
[39]KNEBEL C,HEISE T,ZANGER U M,et al.The azole fungicide tebuconazole affects human CYP1A1 and CYP1A2 expression by an aryl hydrocarbon receptordependent pathway[J].Food Chem Toxicol,2019,123:481-491.
[40]FAHRNER R,MLLER A,PRESS A T,et al.Short-term treatment with taurolidine is associated with liver injury[J].BMC Pharmacol Toxicol,2017,18(1):61.
[41]DONGA X,FU J,YIN X,et al.Induction of apoptosis in HepaRG cell line by aloe-emodin through generation of reactive oxygen species and the mitochondrial pathway[J].Cell Physiol Biochem,2017,42(2):685-696.
[42]FERRON P J,HOGEVEEN K,DE SOUSA G,et al.Modulation of CYP3A4 activity alters the cytotoxicity of lipophilic phycotoxins in human hepatic HepaRG cells[J].Toxicol In Vitro,2016,33:136-146.
[43]BURBAN A,SHARANEK A,GUGUEN-GUILLOUZO C,et al.Endoplasmic reticulum stress precedes oxidative stress in antibiotic-induced cholestasis and cytotoxicity in human hepatocytes[J].Free Radic Biol Med,2018,115:166-178.
[44]BURBANK M G,SHARANEK A,BURBAN A,et al.Mechanistic Insights in cytotoxic and cholestatic potential of the endothelial receptor antagonists using HepaRG cells[J].Toxicol Sci,2017,157(2):451-464.
[45]SHARANEK A,BURBAN A,HUMBERT L,et al.Progressive and preferential cellular accumulation of hydrophobic bile acids induced by cholestatic drugs is associated with inhibition of their amidation and sulfation[J].Drug Metab Dispos,2017,45(12):1292-1303.
[46]TOMIDA T,ISHIMURA M,IWAKI M.A cell-based assay using HepaRG cells for predicting drug-induced phospholipidosis[J].Toxicol Sci,2017,42(5):641-650.
[47]PANT A,RONDINI E A,KOCAREK T A.Farnesol induces fatty acid oxidation and decreases triglyceride accumulation in steatotic HepaRG cells[J].Toxicol Appl Pharmacol,2019,365(15):61-70.
[48]GAO X,LIU Y.A transcriptomic study suggesting human i PSC-derived hepatocytes potentially offer a better in vitro model of hepatotoxicity than most hepatoma cell lines[J].Cell Biol Toxicol,2017,33(4):407-421.