Login Register Cart 0
Research Article

Granzyme B and miR-378a Interaction in Acetaminophen Toxicity in Children

Author(s): Sandra McCullough, Harsh Dweep, Mitchell R. McGill, Sudeepa Bhattacharyya, Laura James, Sara Frankowski, Aaron Woodall, Gregory Kearns and Pritmohinder Gill*

Volume 9, Issue 2, 2020

Page: [121 - 132] Pages: 12

DOI: 10.2174/2211536608666190808144456

open access plus

Abstract

Background and Aim: Hepatic phase I drug-metabolizing enzymes CYP2E1, CYP1A2 and CYP3A4 catalyze the biotransformation of Acetaminophen (APAP) and are important in the mediation of toxicity. The potential role of other hepatic and non-hepatic Phase I enzymes in APAP toxicity has not been established.

Methods: PCR array containing 84 genes involved in phase I drug metabolism was examined in subgroups of hospitalized children for APAP overdose, categorized as no toxicity (ALT ≤ 45 IU/L, n=5) and moderate toxicity (ALT ≥ 500 IU/L, n=5).

Results: Significant downregulation was observed for ALDH6A1, CYP4F12 and GZMB in the no toxicity subgroup and ALDH1A1, CYP27A1 and GZMB in the moderate toxicity subgroup. qRTPCR confirmed significant downregulation for ALDH1A1, CYP4F12, and GZMB. In-silico analysis identified GZMB 3’UTR to be a target of miR-378a-5p. Overexpression of miR-378a-5p reduced the luciferase activity of GZMB 3’UTR reporter plasmid reportedly by 50%. NK-92 cells transfected with the miR-378a-5p mimic extended the effect of APAP on GZMB protein expression compared to mimic controls. In addition, miR-378a-5p was significantly upregulated in blood samples of children with APAP overdose undergoing NAC treatment.

Conclusion: Overall, our study suggests the presence of a novel signaling pathway, whereby miR- 378a-5p inhibits GZMB expression in children with APAP overdose.

Keywords: Acetaminophen (APAP), APAP-Induced Liver Injury (AILI), Cytochrome P450, Granzyme B, miR-378a, biomarkers.

« Previous Next »
Graphical Abstract

[1]
Hinson JA, Roberts DW, James LP. Mechanisms of acetaminophen-induced liver necrosis. Handbook Exp Pharmacol 2010; 196: 369-405.
[http://dx.doi.org/10.1007/978-3-642-00663-0_12] [PMID: 20020268]
[2]
Lee WM. Acetaminophen and the U.S. Acute liver failure study group: lowering the risks of hepatic failure. Hepatology 2004; 40(1): 6-9.
[http://dx.doi.org/10.1002/hep.20293] [PMID: 15239078]
[3]
Ostapowicz G, Fontana RJ, Schiødt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002; 137(12): 947-54.
[http://dx.doi.org/10.7326/0003-4819-137-12-200212170-00007] [PMID: 12484709]
[4]
Dahlin DC, Miwa GT, Lu AY, Nelson SD. N-acetyl-p-benzoquinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen. Proc Natl Acad Sci USA 1984; 81(5): 1327-31.
[http://dx.doi.org/10.1073/pnas.81.5.1327] [PMID: 6424115]
[5]
Ambros V. The functions of animal microRNAs. Nature 2004; 431(7006): 350-5.
[http://dx.doi.org/10.1038/nature02871] [PMID: 15372042]
[6]
Ivey KN, Srivastava D. MicroRNAs as regulators of differentiation and cell fate decisions. Cell Stem Cell 2010; 7(1): 36-41.
[http://dx.doi.org/10.1016/j.stem.2010.06.012] [PMID: 20621048]
[7]
Li Y, Shi X. MicroRNAs in the regulation of TLR and RIG-I pathways. Cell Mol Immunol 2013; 10(1): 65-71.
[http://dx.doi.org/10.1038/cmi.2012.55] [PMID: 23262976]
[8]
O’Connell RM, Rao DS, Chaudhuri AA, Baltimore D. Physiological and pathological roles for microRNAs in the immune system. Nat Rev Immunol 2010; 10(2): 111-22.
[http://dx.doi.org/10.1038/nri2708] [PMID: 20098459]
[9]
Krek A, Grün D, Poy MN, et al. Combinatorial microRNA target predictions. Nat Genet 2005; 37(5): 495-500.
[http://dx.doi.org/10.1038/ng1536] [PMID: 15806104]
[10]
Vliegenthart AD, Shaffer JM, Clarke JI, et al. Comprehensive microRNA profiling in acetaminophen toxicity identifies novel circulating biomarkers for human liver and kidney injury. Sci Rep 2015; 5: 15501.
[http://dx.doi.org/10.1038/srep15501] [PMID: 26489516 ]
[11]
Ward J, Kanchagar C, Veksler-Lublinsky I, et al. Circulating microRNA profiles in human patients with acetaminophen hepatotoxicity or ischemic hepatitis. Proc Natl Acad Sci USA 2014; 111(33): 12169-74.
[http://dx.doi.org/10.1073/pnas.1412608111] [PMID: 25092309]
[12]
Yang X, Salminen WF, Shi Q, et al. Potential of extracellular microRNAs as biomarkers of acetaminophen toxicity in children. Toxicol Appl Pharmacol 2015; 284(2): 180-7.
[http://dx.doi.org/10.1016/j.taap.2015.02.013] [PMID: 25708609]
[13]
Antoine DJ, Dear JW, Lewis PS, et al. Mechanistic biomarkers provide early and sensitive detection of acetaminophen-induced acute liver injury at first presentation to hospital. Hepatology 2013; 58(2): 777-87.
[http://dx.doi.org/10.1002/hep.26294] [PMID: 23390034]
[14]
Dear JW, Antoine DJ, Starkey-Lewis P, Goldring CE, Park BK. Early detection of paracetamol toxicity using circulating liver microRNA and markers of cell necrosis. Br J Clin Pharmacol 2014; 77(5): 904-5.
[http://dx.doi.org/10.1111/bcp.12214] [PMID: 23879521]
[15]
Jetten MJ, Gaj S, Ruiz-Aracama A, et al. 'Omics analysis of low dose acetaminophen intake demonstrates novel response pathways in humans. Toxicol Appl Pharmacol 2012; 259(3): 320-8.
[http://dx.doi.org/10.1016/j.taap.2012.01.009] [PMID: 22285215]
[16]
Krauskopf J, de Kok TM, Schomaker SJ, et al. Serum microRNA signatures as “liquid biopsies” for interrogating hepatotoxic mechanisms and liver pathogenesis in human. PLoS One 2017; 12(5) e0177928
[http://dx.doi.org/10.1371/journal.pone.0177928] [PMID: 28545106]
[17]
Starkey Lewis PJ, Merz M, Couttet P, et al. Serum microRNA biomarkers for drug-induced liver injury. Clin Pharmacol Ther 2012; 92(3): 291-3.
[http://dx.doi.org/10.1038/clpt.2012.101] [PMID: 22828715]
[18]
Yu AM, Tian Y, Tu MJ, Ho PY, Jilek JL. MicroRNA pharmacoepigenetics: posttranscriptional regulation mechanisms behind variable drug disposition and strategy to develop more effective therapy. Drug Metab Dispos 2016; 44(3): 308-19.
[http://dx.doi.org/10.1124/dmd.115.067470] [PMID: 26566807]
[19]
Chowdhary V, Teng KY, Thakral S, et al. miRNA-122 protects mice and human hepatocytes from acetaminophen toxicity by regulating cytochrome P450 family 1 subfamily A member 2 and family 2 subfamily E member 1 expression. Am J Pathol 2017; 187(12): 2758-74.
[http://dx.doi.org/10.1016/j.ajpath.2017.08.026] [PMID: 28963035]
[20]
Gill P, Bhattacharyya S, McCullough S, et al. MicroRNA regulation of CYP 1A2, CYP3A4 and CYP2E1 expression in acetaminophen toxicity. Sci Rep 2017; 7(1): 12331.
[http://dx.doi.org/10.1038/s41598-017-11811-y] [PMID: 28951593]
[21]
Yu D, Wu L, Gill P, et al. Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol 2018; 92(2): 845-58.
[http://dx.doi.org/10.1007/s00204-017-2090-y] [PMID: 29067470]
[22]
Bhattacharyya S, Yan K, Pence L, et al. Targeted liquid chromatography-mass spectrometry analysis of serum acylcarnitines in acetaminophen toxicity in children. Biomarkers Med 2014; 8(2): 147-59.
[http://dx.doi.org/10.2217/bmm.13.150] [PMID: 24521011]
[23]
Khandelwal N, James LP, Sanders C, Larson AM, Lee WM. Unrecognized acetaminophen toxicity as a cause of indeterminate acute liver failure. Hepatology 2011; 53(2): 567-76.
[http://dx.doi.org/10.1002/hep.24060] [PMID: 21274877]
[24]
Muldrew KL, James LP, Coop L, et al. Determination of acetaminophen-protein adducts in mouse liver and serum and human serum after hepatotoxic doses of acetaminophen using high-performance liquid chromatography with electrochemical detection. Drug Metab Dispos 2002; 30(4): 446-51.
[http://dx.doi.org/10.1124/dmd.30.4.446] [PMID: 11901099]
[25]
Arikawa E, Sun Y, Wang J, et al. Cross-platform comparison of SYBR Green real-time PCR with TaqMan PCR, microarrays and other gene expression measurement technologies evaluated in the MicroArray Quality Control (MAQC) study. BMC Genomics 2008; 9: 328.
[http://dx.doi.org/10.1186/1471-2164-9-328] [PMID: 18620571]
[26]
Paraskevopoulou MD, Georgakilas G, Kostoulas N, et al. DIANA-microT web server v5.0: service integration into miRNA functional analysis workflows. Nucleic Acids Res 2013; 41: 169-73.
[http://dx.doi.org/10.1093/nar/gkt393]
[27]
Dweep H, Gretz N. miRWalk2.0: a comprehensive atlas of microRNA-target interactions. Nat Methods 2015; 12(8): 697.
[http://dx.doi.org/10.1038/nmeth.3485] [PMID: 26226356]
[28]
Dweep H, Sticht C, Pandey P, Gretz N. miRWalk--database: prediction of possible miRNA binding sites by “walking” the genes of three genomes. J Biomed Inform 2011; 44(5): 839-47.
[http://dx.doi.org/10.1016/j.jbi.2011.05.002] [PMID: 21605702]
[29]
Battle A, Brown CD, Engelhardt BE, Montgomery SB. Genetic effects on gene expression across human tissues. Nature 2017; 550(7675): 204-13.
[http://dx.doi.org/10.1038/nature24277] [PMID: 29022597]
[30]
Leidinger P, Backes C, Meder B, Meese E, Keller A. The human miRNA repertoire of different blood compounds. BMC Genomics 2014; 15: 474.
[http://dx.doi.org/10.1186/1471-2164-15-474] [PMID: 24928098]
[31]
Mitchell JR, Jollow DJ, Potter WZ, Gillette JR, Brodie BB. Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. J Pharmacol Exp Ther 1973; 187(1): 211-7.
[PMID: 4746329]
[32]
Han D, Dara L, Win S, et al. Regulation of drug-induced liver injury by signal transduction pathways: critical role of mitochondria. Trends Pharmacol Sci 2013; 34(4): 243-53.
[http://dx.doi.org/10.1016/j.tips.2013.01.009] [PMID: 23453390]
[33]
James LP, Mayeux PR, Hinson JA. Acetaminophen-induced hepatotoxicity. Drug Metab Dispos 2003; 31(12): 1499-506.
[http://dx.doi.org/10.1124/dmd.31.12.1499] [PMID: 14625346]
[34]
Hinson JA, Pike SL, Pumford NR, Mayeux PR. Nitrotyrosine-protein adducts in hepatic centrilobular areas following toxic doses of acetaminophen in mice. Chem Res Toxicol 1998; 11(6): 604-7.
[http://dx.doi.org/10.1021/tx9800349] [PMID: 9625727]
[35]
James LP, Letzig L, Simpson PM, et al. Pharmacokinetics of acetaminophen-protein adducts in adults with acetaminophen overdose and acute liver failure. Drug Metab Dispos 2009; 37(8): 1779-84.
[http://dx.doi.org/10.1124/dmd.108.026195] [PMID: 19439490]
[36]
Du K, Ramachandran A, Jaeschke H. Oxidative stress during acetaminophen hepatotoxicity: sources, pathophysiological role and therapeutic potential. Redox Biol 2016; 10: 148-56.
[http://dx.doi.org/10.1016/j.redox.2016.10.001] [PMID: 27744120]
[37]
Gonçalves DF, de Carvalho NR, Leite MB, et al. Caffeine and acetaminophen association: effects on mitochondrial bioenergetics. Life Sci 2018; 193: 234-41.
[http://dx.doi.org/10.1016/j.lfs.2017.10.039] [PMID: 29107792]
[38]
Hanawa N, Shinohara M, Saberi B, Gaarde WA, Han D, Kaplowitz N. Role of JNK translocation to mitochondria leading to inhibition of mitochondria bioenergetics in acetaminophen-induced liver injury. J Biol Chem 2008; 283(20): 13565-77.
[http://dx.doi.org/10.1074/jbc.M708916200] [PMID: 18337250]
[39]
Jaeschke H, McGill MR, Ramachandran A. Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity. Drug Metab Rev 2012; 44(1): 88-106.
[http://dx.doi.org/10.3109/03602532.2011.602688] [PMID: 22229890]
[40]
Adams ML, Pierce RH, Vail ME, et al. Enhanced acetaminophen hepatotoxicity in transgenic mice overexpressing BCL-2. Mol Pharmacol 2001; 60(5): 907-15.
[http://dx.doi.org/10.1124/mol.60.5.907] [PMID: 11641418]
[41]
Bajt ML, Farhood A, Lemasters JJ, Jaeschke H. Mitochondrial bax translocation accelerates DNA fragmentation and cell necrosis in a murine model of acetaminophen hepatotoxicity. J Pharmacol Exp Ther 2008; 324(1): 8-14.
[http://dx.doi.org/10.1124/jpet.107.129445] [PMID: 17906064]
[42]
El-Hassan H, Anwar K, Macanas-Pirard P, et al. Involvement of mitochondria in acetaminophen-induced apoptosis and hepatic injury: roles of cytochrome C, Bax, Bid, and caspases. Toxicol Appl Pharmacol 2003; 191(2): 118-29.
[http://dx.doi.org/10.1016/S0041-008X(03)00240-0] [PMID: 12946648]
[43]
Gunawan BK, Liu ZX, Han D, Hanawa N, Gaarde WA, Kaplowitz N. c-Jun N-terminal kinase plays a major role in murine acetaminophen hepatotoxicity. Gastroenterology 2006; 131(1): 165-78.
[http://dx.doi.org/10.1053/j.gastro.2006.03.045] [PMID: 16831600]
[44]
Ludwig N, Leidinger P, Becker K, et al. Distribution of miRNA expression across human tissues. Nucleic Acids Res 2016; 44(8): 3865-77.
[http://dx.doi.org/10.1093/nar/gkw116] [PMID: 26921406]
[45]
Carrer M, Liu N, Grueter CE, et al. Control of mitochondrial metabolism and systemic energy homeostasis by microRNAs 378 and 378*. Proc Natl Acad Sci USA 2012; 109(38): 15330-5.
[http://dx.doi.org/10.1073/pnas.1207605109] [PMID: 22949648]
[46]
Eichner LJ, Perry MC, Dufour CR, et al. miR-378(*) mediates metabolic shift in breast cancer cells via the PGC-1β/ERRγ transcriptional pathway. Cell Metab 2010; 12(4): 352-61.
[http://dx.doi.org/10.1016/j.cmet.2010.09.002] [PMID: 20889127]
[47]
Crome SQ, Lang PA, Lang KS, Ohashi PS. Natural killer cells regulate diverse T cell responses. Trends Immunol 2013; 34(7): 342-9.
[http://dx.doi.org/10.1016/j.it.2013.03.002] [PMID: 23601842]
[48]
Pallmer K, Oxenius A. Recognition and regulation of T Cells by NK Cells. Front Immunol 2016; 7: 251.
[http://dx.doi.org/10.3389/fimmu.2016.00251] [PMID: 27446081]
[49]
Krist B, Florczyk U, Pietraszek-Gremplewicz K, Józkowicz A, Dulak J. The role of miR-378a in metabolism, angiogenesis, and muscle biology. Int J Endocrinol 2015; 2015281756
[http://dx.doi.org/10.1155/2015/281756] [PMID: 26839547]
[50]
Wang P, Gu Y, Zhang Q, et al. Identification of resting and type I IFN-activated human NK cell miRNomes reveals microRNA-378 and microRNA-30e as negative regulators of NK cell cytotoxicity. J Immunol 2012; 189(1): 211-21.
[http://dx.doi.org/10.4049/jimmunol.1200609] [PMID: 22649192]
[51]
Elavazhagan S, Fatehchand K, Santhanam V, et al. Granzyme B expression is enhanced in human monocytes by TLR8 agonists and contributes to antibody-dependent cellular cytotoxicity. J Immunol 2015; 194(6): 2786-95.
[http://dx.doi.org/10.4049/jimmunol.1402316] [PMID: 25667415]
[52]
Liu S, Chen L, Zeng Y, et al. Suppressed expression of miR-378 targeting GZMB in NK cells is required to control dengue virus infection. Cell Mol Immunol 2016; 13(5): 700-8.
[http://dx.doi.org/10.1038/cmi.2015.52] [PMID: 26166761]
[53]
Bhise NS, Chauhan L, Shin M, et al. MicroRNA-mRNA pairs associated with outcome in AML: from in vitro cell-based studies to AML patients. Front Pharmacol 2016; 6: 324.
[http://dx.doi.org/10.3389/fphar.2015.00324] [PMID: 26858643]
[54]
Consortium GT. The Genotype-Tissue Expression (GTEx) project. Nat Genet 2013; 45(6): 580-5.
[http://dx.doi.org/10.1038/ng.2653] [PMID: 23715323]
[55]
Wilhelm M, Schlegl J, Hahne H, et al. Mass-spectrometry-based draft of the human proteome. Nature 2014; 509(7502): 582-7.
[http://dx.doi.org/10.1038/nature13319] [PMID: 24870543]
[56]
Chiusolo V, Jacquemin G, Yonca Bassoy E, et al. Granzyme B enters the mitochondria in a Sam50-, Tim22- and mtHsp70-dependent manner to induce apoptosis. Cell Death Differ 2017; 24(4): 747-58.
[http://dx.doi.org/10.1038/cdd.2017.3] [PMID: 28338658]
[57]
Trapani JA. Immunity, granzymes and cell killing. In: eLS John Wiley and Sons, Ltd. 2001.
[http://dx.doi.org/10.1002/9780470015902]
[58]
Afonina IS, Cullen SP, Martin SJ. Cytotoxic and non-cytotoxic roles of the CTL/NK protease granzyme B. Immunol Rev 2010; 235(1): 105-16.
[http://dx.doi.org/10.1111/j.0105-2896.2010.00908.x] [PMID: 20536558]
[59]
Cullen SP, Brunet M, Martin SJ. Granzymes in cancer and immunity. Cell Death Differ 2010; 17(4): 616-23.
[http://dx.doi.org/10.1038/cdd.2009.206] [PMID: 20075940 ]
[60]
Davis JE, Sutton VR, Smyth MJ, Trapani JA. Dependence of granzyme B-mediated cell death on a pathway regulated by Bcl-2 or its viral homolog, BHRF1. Cell Death Differ 2000; 7(10): 973-83.
[http://dx.doi.org/10.1038/sj.cdd.4400725] [PMID: 11279544]
[61]
Jacquemin G, Margiotta D, Kasahara A, et al. Granzyme B-induced mitochondrial ROS are required for apoptosis. Cell Death Differ 2015; 22(5): 862-74.
[http://dx.doi.org/10.1038/cdd.2014.180] [PMID: 25361078]
[62]
Wensink AC, Hack CE, Bovenschen N. Granzymes regulate pro inflammatory cytokine responses. J Immunol 2015; 194(2): 491-7.
[http://dx.doi.org/10.4049/jimmunol.1401214] [PMID: 25556251]
[63]
Ray SD, Jena N. A hepatotoxic dose of acetaminophen modulates expression of BCL-2, BCL-X(L), and BCL-X(S) during apoptotic and necrotic death of mouse liver cells in vivo. Arch Toxicol 2000; 73(10-11): 594-606.
[http://dx.doi.org/10.1007/s002040050013] [PMID: 10663392]
[64]
Qiu Y, Benet LZ, Burlingame AL. Identification of the hepatic protein targets of reactive metabolites of acetaminophen in vivo in mice using two-dimensional gel electrophoresis and mass spectrometry. J Biol Chem 1998; 273(28): 17940-53.
[http://dx.doi.org/10.1074/jbc.273.28.17940] [PMID: 9651401]
[65]
Donnelly PJ, Walker RM, Racz WJ. Inhibition of mitochondrial respiration in vivo is an early event in acetaminophen-induced hepatotoxicity. Arch Toxicol 1994; 68(2): 110-8.
[http://dx.doi.org/10.1007/s002040050043] [PMID: 8179480]
[66]
Boulares AH, Zoltoski AJ, Stoica BA, Cuvillier O, Smulson ME. Acetaminophen induces a caspase-dependent and Bcl-XL sensitive apoptosis in human hepatoma cells and lymphocytes. Pharmacol Toxicol 2002; 90(1): 38-50.
[http://dx.doi.org/10.1034/j.1600-0773.2002.900108.x] [PMID: 12005112]
[67]
Krenkel O, Mossanen JC, Tacke F. Immune mechanisms in acetaminophen-induced acute liver failure. Hepatobiliary Surg Nutr 2014; 3(6): 331-43.
[http://dx.doi.org/10.3978/j.issn.2304-3881.2014.11.01] [PMID: 25568858]
[68]
Liu ZX, Govindarajan S, Kaplowitz N. Innate immune system plays a critical role in determining the progression and severity of acetaminophen hepatotoxicity. Gastroenterology 2004; 127(6): 1760-74.
[http://dx.doi.org/10.1053/j.gastro.2004.08.053] [PMID: 15578514]
[69]
Yee SB, Bourdi M, Masson MJ, Pohl LR. Hepatoprotective role of endogenous interleukin-13 in a murine model of acetaminophen-induced liver disease. Chem Res Toxicol 2007; 20(5): 734-44.
[http://dx.doi.org/10.1021/tx600349f] [PMID: 17439248]
[70]
Jaeschke H, Duan L, Akakpo JY, Farhood A, Ramachandran A. The role of apoptosis in acetaminophen hepatotoxicity. Food Chem Toxicol 2018; 118: 709-18.
[http://dx.doi.org/10.1016/j.fct.2018.06.025] [PMID: 29920288]
[71]
Ramachandran A, McGill MR, Xie Y, Ni HM, Ding WX, Jaeschke H. Receptor interacting protein kinase 3 is a critical early mediator of acetaminophen-induced hepatocyte necrosis in mice. Hepatology 2013; 58(6): 2099-108.
[http://dx.doi.org/10.1002/hep.26547] [PMID: 23744808]
[72]
Masson MJ, Carpenter LD, Graf ML, Pohl LR. Pathogenic role of natural killer T and natural killer cells in acetaminophen-induced liver injury in mice is dependent on the presence of dimethyl sulfoxide. Hepatology 2008; 48(3): 889-97.
[http://dx.doi.org/10.1002/hep.22400] [PMID: 18712839]
[73]
Ida H, Utz PJ, Anderson P, Eguchi K. Granzyme B and Natural Killer (NK) cell death. Mod Rheumatol 2005; 15(5): 315-22.
[http://dx.doi.org/10.3109/s10165-005-0426-6] [PMID: 17029086]
[74]
Rousalova I, Krepela E. Granzyme B-induced apoptosis in cancer cells and its regulation. Int J Oncol 2010; 37(6): 1361-78.
[PMID: 21042704]

Rights & Permissions Print Cite
Article Metrics
35
7
© 2024 Bentham Science Publishers | Privacy Policy