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The endoplasmic reticulum participated in drug metabolic toxicity

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Abstract

Covalent binding of reactive metabolites formed by drug metabolic activation with biological macromolecules is considered to be an important mechanism of drug metabolic toxicity. Recent studies indicate that the endoplasmic reticulum (ER) could play an important role in drug toxicity by participating in the metabolic activation of drugs and could be a primarily attacked target by reactive metabolites. In this article, we summarize the generation and mechanism of reactive metabolites in ER stress and their associated cell death and inflammatory cascade, as well as the systematic modulation of unfolded protein response (UPR)-mediated adaptive pathways.

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References

  • Alcorn N, Saunders S, Madhok R. Benefit-risk assessment of leflunomide: an appraisal of leflunomide in rheumatoid arthritis 10 years after licensing. Drug Saf. 2009;32(12):1123–34.

    Article  CAS  Google Scholar 

  • Almansour MI, Jarrar YB, Jarrar BM. In vivo investigation on the chronic hepatotoxicity induced by sertraline. Environ Toxicol Pharmacol. 2018;61:107–15.

    Article  CAS  Google Scholar 

  • Attia SM. Deleterious effects of reactive metabolites. Oxid Med Cell Longev. 2010;3(4):238–53.

    Article  Google Scholar 

  • Bacher S, et al. Regulation of transcription factor NF-kappaB in its natural habitat: the nucleus. Cells. 2021;10(4).

  • Balchin D, Hayer-Hartl M, Hartl FU. Recent advances in understanding catalysis of protein folding by molecular chaperones. FEBS Lett. 2020;594(17):2770–81.

    Article  CAS  Google Scholar 

  • Berridge MJ. Calcium signalling remodelling and disease. Biochem Soc Trans. 2012;40(2):297–309.

    Article  CAS  Google Scholar 

  • Bialik S, Dasari SK, Kimchi A. Autophagy-dependent cell death - where, how and why a cell eats itself to death. J Cell Sci. 2018. 131(18).

  • Boelsterli UA, Lee KK. Mechanisms of isoniazid-induced idiosyncratic liver injury: emerging role of mitochondrial stress. J Gastroenterol Hepatol. 2014;29(4):678–87.

    Article  CAS  Google Scholar 

  • Bosch ME, Kielian T. Neuroinflammatory paradigms in lysosomal storage diseases. Front Neurosci. 2015;9:417.

    Article  Google Scholar 

  • Butler LE, et al. The calcium-binding protein calreticulin is covalently modified in rat liver by a reactive metabolite of the inhalation anesthetic halothane. Chem Res Toxicol. 1992;5(3):406–10.

    Article  CAS  Google Scholar 

  • Cai T, Yao L, Turesky RJ. Bioactivation of heterocyclic aromatic amines by UDP glucuronosyltransferases. Chem Res Toxicol. 2016;29(5):879–91.

    Article  CAS  Google Scholar 

  • Cao SS, Luo KL, Shi L. Endoplasmic reticulum stress interacts with inflammation in human diseases. J Cell Physiol. 2016;231(2):288–94.

    Article  CAS  Google Scholar 

  • Cao T, et al. Integrated signaling system under endoplasmic reticulum stress in eukaryotic microorganisms. Appl Microbiol Biotechnol. 2021;105(12):4805–18.

    Article  CAS  Google Scholar 

  • Cashman JR, et al. N-oxygenation of amphetamine and methamphetamine by the human flavin-containing monooxygenase (form 3): role in bioactivation and detoxication. J Pharmacol Exp Ther. 1999;288(3):1251–60.

    CAS  Google Scholar 

  • Chakravarthi S, Jessop CE, Bulleid NJ. The role of glutathione in disulphide bond formation and endoplasmic-reticulum-generated oxidative stress. EMBO reports. 2006;7(3):271–5.

    Article  CAS  Google Scholar 

  • Chen S, et al. Sertraline induces endoplasmic reticulum stress in hepatic cells. Toxicology. 2014;322:78–88.

    Article  CAS  Google Scholar 

  • Chen HC, et al. An interconnected hierarchical model of cell death regulation by the BCL-2 family. Nat Cell Biol. 2015;17(10):1270–81.

    Article  CAS  Google Scholar 

  • Chen S, et al. The role of hepatic cytochrome P450s in the cytotoxicity of sertraline. Arch Toxicol. 2020;94(7):2401–11.

    Article  Google Scholar 

  • Cheng L, et al. Involvement of natural killer T cells in halothane-induced liver injury in mice. Biochem Pharmacol. 2010;80(2):255–61.

    Article  CAS  Google Scholar 

  • Chong WC, et al. The complex interplay between endoplasmic reticulum stress and the NLRP3 inflammasome: a potential therapeutic target for inflammatory disorders. Clin Transl Immunology. 2021;10(2):e1247.

    Article  CAS  Google Scholar 

  • Cribb AE, et al. The endoplasmic reticulum in xenobiotic toxicity. Drug Metab Rev. 2005;37(3):405–42.

    Article  CAS  Google Scholar 

  • Cybulsky AV. Endoplasmic reticulum stress, the unfolded protein response and autophagy in kidney diseases. Nat Rev Nephrol. 2017;13(11):681–96.

    Article  CAS  Google Scholar 

  • Dara L, Ji C, Kaplowitz N. The contribution of endoplasmic reticulum stress to liver diseases. Hepatology. 2011;53(5):1752–63.

    Article  CAS  Google Scholar 

  • Dasari SK, et al. Signalome-wide RNAi screen identifies GBA1 as a positive mediator of autophagic cell death. Cell Death and Differentiation. 2017;24(7):1288–302.

    Article  CAS  Google Scholar 

  • den Braver MW, et al. Characterization of cytochrome P450 isoforms involved in sequential two-step bioactivation of diclofenac to reactive p-benzoquinone imines. Toxicol Lett. 2016;253:46–54.

    Article  Google Scholar 

  • Deng J, et al. Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2. Mol Cell Biol. 2004;24(23):10161–8.

    Article  CAS  Google Scholar 

  • Dhanasekaran DN, Reddy EP. JNK signaling in apoptosis. Oncogene. 2008;27(48):6245–51.

    Article  CAS  Google Scholar 

  • Eggleton P, et al. Calreticulin, a therapeutic target? Expert Opin Ther Targets. 2016;20(9):1137–47.

    Article  CAS  Google Scholar 

  • Galluzzi L, et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018;25(3):486–541.

    Article  Google Scholar 

  • Gan J, Ma S, Zhang D. Non-cytochrome P450-mediated bioactivation and its toxicological relevance. Drug Metab Rev. 2016;48(4):473–501.

    Article  CAS  Google Scholar 

  • Ganta KK, Chaubey B. Endoplasmic reticulum stress leads to mitochondria-mediated apoptosis in cells treated with anti-HIV protease inhibitor ritonavir. Cell Biol Toxicol. 2019;35(3):189–204.

    Article  Google Scholar 

  • Glass CK, et al. Mechanisms underlying inflammation in neurodegeneration. Cell. 2010;140(6):918–34.

    Article  CAS  Google Scholar 

  • Gramec D, Peterlin Mašič L, Sollner Dolenc M. Bioactivation potential of thiophene-containing drugs. Chem Res Toxicol. 2014;27(8):1344–58.

    Article  CAS  Google Scholar 

  • Grootjans J, et al. The unfolded protein response in immunity and inflammation. Nat Rev Immunol. 2016;16(8):469–84.

    Article  CAS  Google Scholar 

  • Guengerich FP. Cytochrome P450 2E1 and its roles in disease. Chem Biol Interact. 2020;322:109056.

    Article  CAS  Google Scholar 

  • Guo HL, et al. Pyrazinamide-induced hepatotoxicity is alleviated by 4-PBA via inhibition of the PERK-eIF2alpha-ATF4-CHOP pathway. Toxicology. 2017;378:65–75.

    Article  CAS  Google Scholar 

  • Halliday M, Hughes D, Mallucci GR. Fine-tuning PERK signaling for neuroprotection. J Neurochem. 2017;142(6):812–26.

    Article  CAS  Google Scholar 

  • Harjumäki R, Pridgeon CS, Ingelman-Sundberg M. CYP2E1 in alcoholic and non-alcoholic liver injury. Roles of ROS, reactive intermediates and lipid overload. Int J Mol Sci. 2021;22:15.

    Article  Google Scholar 

  • Hartman JH, et al. Subcellular localization of rat CYP2E1 impacts metabolic efficiency toward common substrates. Toxicology. 2015;338:47–58.

    Article  CAS  Google Scholar 

  • Hata AN, Engelman JA, Faber AC. The BCL2 family: key mediators of the apoptotic response to targeted anticancer therapeutics. Cancer Discov. 2015;5(5):475–87.

    Article  CAS  Google Scholar 

  • Hatahet F, Ruddock LW. Protein disulfide isomerase: a critical evaluation of its function in disulfide bond formation. Antioxid Redox Signal. 2009;11(11):2807–50.

    Article  CAS  Google Scholar 

  • Hebert DN, Molinari M. In and out of the ER: protein folding, quality control, degradation, and related human diseases. Physiol Rev. 2007;87(4):1377–408.

    Article  CAS  Google Scholar 

  • Henderson MC, et al. Human flavin-containing monooxygenase form 2 S-oxygenation: sulfenic acid formation from thioureas and oxidation of glutathione. Chem Res Toxicol. 2004;17(5):633–40.

    Article  CAS  Google Scholar 

  • Heneka MT, Kummer MP, Latz E. Innate immune activation in neurodegenerative disease. Nat Rev Immunol. 2014;14(7):463–77.

    Article  CAS  Google Scholar 

  • Hervas R, Oroz J. Mechanistic insights into the role of molecular chaperones in protein misfolding diseases: from molecular recognition to amyloid disassembly. Int J Mol Sci. 2020;21(23).

  • Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol. 2012;13(2):89–102.

    Article  CAS  Google Scholar 

  • Hetz C, Papa FR. The unfolded protein response and cell fate control. Mol Cell. 2018;69(2):169–81.

    Article  CAS  Google Scholar 

  • Hetz C, Chevet E, Harding HP. Targeting the unfolded protein response in disease. Nat Rev Drug Discov. 2013;12(9):703–19.

    Article  CAS  Google Scholar 

  • Hillary RF, FitzGerald U. A lifetime of stress: ATF6 in development and homeostasis. J Biomed Sci. 2018;25(1):48.

    Article  Google Scholar 

  • Hollien J, Weissman JS. Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science. 2006;313(5783):104–7.

    Article  CAS  Google Scholar 

  • Hu P, et al. Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1alpha-mediated NF-kappaB activation and down-regulation of TRAF2 expression. Mol Cell Biol. 2006;26(8):3071–84.

    Article  CAS  Google Scholar 

  • Hu H, et al. The C/EBP homologous protein (CHOP) transcription factor functions in endoplasmic reticulum stress-induced apoptosis and microbial infection. Front Immunol. 2018;9:3083.

    Article  CAS  Google Scholar 

  • Hutzler JM, et al. Mechanism-based inactivation of cytochrome P450 2C9 by tienilic acid and (+/-)-suprofen: a comparison of kinetics and probe substrate selection. Drug Metab Dispos. 2009;37(1):59–65.

    Article  CAS  Google Scholar 

  • Ibarra MC, et al. Malignant hyperthermia in Japan: mutation screening of the entire ryanodine receptor type 1 gene coding region by direct sequencing. Anesthesiology. 2006;104(6):1146–54.

    Article  Google Scholar 

  • Igbaria A, et al. Chaperone-mediated reflux of secretory proteins to the cytosol during endoplasmic reticulum stress. Proc Natl Acad Sci U S A. 2019;116(23):11291–8.

    Article  CAS  Google Scholar 

  • Ikehata K, et al. Protein targets of reactive metabolites of thiobenzamide in rat liver in vivo. Chem Res Toxicol. 2008;21(7):1432–42.

    Article  CAS  Google Scholar 

  • Iurlaro R, Muñoz-Pinedo C. Cell death induced by endoplasmic reticulum stress. The FEBS Journal. 2016;283(14):2640–52.

    Article  CAS  Google Scholar 

  • Jia ZL, et al. Mechanism of isoniazid-induced hepatotoxicity in zebrafish larvae: activation of ROS-mediated ERS, apoptosis and the Nrf2 pathway. Chemosphere. 2019;227:541–50.

    Article  CAS  Google Scholar 

  • Jia R, Oda S, Yokoi T. Pharmacological evidence for the involvement of ryanodine receptors in halothane-induced liver injury in mice. Toxicology. 2020;443:152560.

    Article  CAS  Google Scholar 

  • Jung KT, Oh SH. Polyubiquitination of p62/SQSTM1 is a prerequisite for Fas/CD95 aggregation to promote caspase-dependent apoptosis in cadmium-exposed mouse monocyte RAW264.7 cells. Scientific Reports. 2019;9:13.

    Google Scholar 

  • Kalgutkar AS, et al. A comprehensive listing of bioactivation pathways of organic functional groups. Curr Drug Metab. 2005;6(3):161–225.

    Article  CAS  Google Scholar 

  • Kaplan C, Zhang Y. Assessing the comparative-effectiveness of antidepressants commonly prescribed for depression in the US Medicare population. J Ment Health Policy Econ. 2012;15(4):171–8.

    Google Scholar 

  • Khan AA, et al. Biochemical and pathological studies on peroxidases -an updated review. Glob J Health Sci. 2014;6(5):87–98.

    Article  Google Scholar 

  • Kim I, Xu W, Reed JC. Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat Rev Drug Discov. 2008;7(12):1013–30.

    Article  CAS  Google Scholar 

  • Lange PS, et al. ATF4 is an oxidative stress-inducible, prodeath transcription factor in neurons in vitro and in vivo. J Exp Med. 2008;205(5):1227–42.

    Article  CAS  Google Scholar 

  • Lerner AG, et al. IRE1α induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress. Cell Metabolism. 2012;16(2):250–64.

    Article  CAS  Google Scholar 

  • Li G, et al. Role of ERO1-alpha-mediated stimulation of inositol 1,4,5-triphosphate receptor activity in endoplasmic reticulum stress-induced apoptosis. J Cell Biol. 2009;186(6):783–92.

    Article  CAS  Google Scholar 

  • Li G, et al. NADPH oxidase links endoplasmic reticulum stress, oxidative stress, and PKR activation to induce apoptosis. J Cell Biol. 2010;191(6):1113–25.

    Article  CAS  Google Scholar 

  • Liao Y, et al. Excessive ER-phagy mediated by the autophagy receptor FAM134B results in ER stress, the unfolded protein response, and cell death in HeLa cells. J Biol Chem. 2019;294(52):20009–23.

    Article  CAS  Google Scholar 

  • Liebler DC, Guengerich FP. Elucidating mechanisms of drug-induced toxicity. Nature Reviews Drug Discovery. 2005;4(5):410–20.

    Article  CAS  Google Scholar 

  • Lien JC, et al. Naphthoquinone derivative PPE8 induces endoplasmic reticulum stress in p53 null H1299 cells. Oxid Med Cell Longev. 2015;2015:453679.

    Article  Google Scholar 

  • Liu J, Lin A. Role of JNK activation in apoptosis: a double-edged sword. Cell Res. 2005;15(1):36–42.

    Article  Google Scholar 

  • Liu H, et al. Protein disulfide isomerase as a novel target for cyclopentenone prostaglandins: implications for hypoxic ischemic injury. FEBS J. 2015;282(10):2045–59.

    Article  CAS  Google Scholar 

  • Liu X, et al. Structure-based reactivity profiles of reactive metabolites with glutathione. Chem Res Toxicol. 2020;33(7):1579–93.

    Article  CAS  Google Scholar 

  • Lobach AR, Uetrecht J. Involvement of myeloperoxidase and NADPH oxidase in the covalent binding of amodiaquine and clozapine to neutrophils: implications for drug-induced agranulocytosis. Chem Res Toxicol. 2014;27(4):699–709.

    Article  CAS  Google Scholar 

  • LoPachin RM, Geohagen BC, Nordstroem LU. Mechanisms of soft and hard electrophile toxicities. Toxicology. 2019;418:62–9.

    Article  CAS  Google Scholar 

  • Lu W, Uetrecht JP. Peroxidase-mediated bioactivation of hydroxylated metabolites of carbamazepine and phenytoin. Drug Metab Dispos. 2008;36(8):1624–36.

    Article  CAS  Google Scholar 

  • Luo X, et al. Obesity induces preadipocyte CD36 expression promoting inflammation via the disruption of lysosomal calcium homeostasis and lysosome function. EBioMedicine. 2020;56:102797.

    Article  Google Scholar 

  • MacIntyre DA, et al. Activator protein 1 is a key terminal mediator of inflammation-induced preterm labor in mice. FASEB J. 2014;28(5):2358–68.

    Article  CAS  Google Scholar 

  • Malhotra JD, et al. Antioxidants reduce endoplasmic reticulum stress and improve protein secretion. Proc Natl Acad Sci U S A. 2008;105(47):18525–30.

    Article  CAS  Google Scholar 

  • Marciniak SJ, et al. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev. 2004;18(24):3066–77.

    Article  CAS  Google Scholar 

  • Martinon F, et al. TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat Immunol. 2010;11(5):411–8.

    Article  CAS  Google Scholar 

  • McCullough KD, et al. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol. 2001;21(4):1249–59.

    Article  CAS  Google Scholar 

  • Michalak M, et al. Calreticulin, a multi-process calcium-buffering chaperone of the endoplasmic reticulum. Biochem J. 2009;417(3):651–66.

    Article  CAS  Google Scholar 

  • Moncan M, et al. Regulation of lipid metabolism by the unfolded protein response. J Cell Mol Med. 2021;25(3):1359–70.

    Article  CAS  Google Scholar 

  • Nakatogawa H. Mechanisms governing autophagosome biogenesis. Nat Rev Mol Cell Biol. 2020;21(8):439–58.

    Article  CAS  Google Scholar 

  • Nicoll CR, et al. Ancestral-sequence reconstruction unveils the structural basis of function in mammalian FMOs. Nat Structural Mol Biol. 2019;27(1):14–24.

    Article  Google Scholar 

  • Palit S, et al. Hesperetin induces apoptosis in breast carcinoma by triggering accumulation of ROS and activation of ASK1/JNK pathway. J Cell Physiol. 2015;230(8):1729–39.

    Article  CAS  Google Scholar 

  • Park BK, et al. The role of metabolic activation in drug-induced hepatotoxicity. Annu Rev Pharmacol Toxicol. 2005;45:177–202.

    Article  CAS  Google Scholar 

  • Ramming T, et al. A PDI-catalyzed thiol-disulfide switch regulates the production of hydrogen peroxide by human Ero1. Free Radic Biol Med. 2015;83:361–72.

    Article  CAS  Google Scholar 

  • Rao RV, Ellerby HM, Bredesen DE. Coupling endoplasmic reticulum stress to the cell death program. Cell Death Differ. 2004;11(4):372–80.

    Article  CAS  Google Scholar 

  • Rao J, et al. C/EBP homologous protein (CHOP) contributes to hepatocyte death via the promotion of ERO1alpha signalling in acute liver failure. Biochem J. 2015;466(2):369–78.

    Article  CAS  Google Scholar 

  • Ren Z, et al. Endoplasmic reticulum stress induction and ERK1/2 activation contribute to nefazodone-induced toxicity in hepatic cells. Toxicol Sci. 2016;154(2):368–80.

    Article  CAS  Google Scholar 

  • Ren Z, et al. Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017;392:11–21.

    Article  CAS  Google Scholar 

  • Rettie AE, Jones JP. Clinical and toxicological relevance of CYP2C9: drug-drug interactions and pharmacogenetics. Annu Rev Pharmacol Toxicol. 2005;45:477–94.

    Article  CAS  Google Scholar 

  • Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 2007;8(7):519–29.

    Article  CAS  Google Scholar 

  • Santos CX, et al. Mechanisms and implications of reactive oxygen species generation during the unfolded protein response: roles of endoplasmic reticulum oxidoreductases, mitochondrial electron transport, and NADPH oxidase. Antioxid Redox Signal. 2009;11(10):2409–27.

    Article  CAS  Google Scholar 

  • Santos CX, et al. Targeted redox inhibition of protein phosphatase 1 by Nox4 regulates eIF2alpha-mediated stress signaling. EMBO J. 2016;35(3):319–34.

    Article  CAS  Google Scholar 

  • Sarcinelli C, et al.. ATF4-dependent NRF2 transcriptional regulation promotes antioxidant protection during endoplasmic reticulum stress. Cancers (Basel). 2020;12(3).

  • Saukkonen JJ, et al. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med. 2006;174(8):935–52.

    Article  CAS  Google Scholar 

  • Seervi M, et al. ROS mediated ER stress induces Bax-Bak dependent and independent apoptosis in response to thioridazine. Biomed Pharmacother. 2018;106:200–9.

    Article  CAS  Google Scholar 

  • Seidel M, Lai FA, Zissimopoulos S. Structural and functional interactions within ryanodine receptor. Biochem Soc Trans. 2015;43(3):377–83.

    Article  CAS  Google Scholar 

  • Sharma RB, Snyder JT, Alonso LC. Atf6alpha impacts cell number by influencing survival, death and proliferation. Mol Metab. 2019;27S:S69–80.

    Article  Google Scholar 

  • Shehu AI, Ma X, Venkataramanan R. Mechanisms of drug-induced hepatotoxicity. Clin Liver Dis. 2017;21(1):35–54.

    Article  Google Scholar 

  • Shen J, et al. ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev Cell. 2002;3(1):99–111.

    Article  CAS  Google Scholar 

  • Shore GC, Papa FR, Oakes SA. Signaling cell death from the endoplasmic reticulum stress response. Curr Opin Cell Biol. 2011;23(2):143–9.

    Article  CAS  Google Scholar 

  • Siddiqui WA, Ahad A, Ahsan H. The mystery of BCL2 family: Bcl-2 proteins and apoptosis: an update. Arch Toxicol. 2015;89(3):289–317.

    Article  CAS  Google Scholar 

  • Song Y, et al. Interaction of nobiletin with methotrexate ameliorates 7-OH methotrexate-induced nephrotoxicity through endoplasmic reticulum stress-dependent PERK/CHOP signaling pathway. Pharmacol Res. 2021;165:105371.

    Article  CAS  Google Scholar 

  • Stachulski AV, et al. The generation, detection, and effects of reactive drug metabolites. Med Res Rev. 2013;33(5):985–1080.

    Article  CAS  Google Scholar 

  • Tabary O, et al. Calcium-dependent regulation of NF-(kappa)B activation in cystic fibrosis airway epithelial cells. Cell Signal. 2006;18(5):652–60.

    Article  CAS  Google Scholar 

  • Tabas I, Ron D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol. 2011;13(3):184–90.

    Article  CAS  Google Scholar 

  • Tafazoli S, O'Brien PJ. Peroxidases: a role in the metabolism and side effects of drugs. Drug Discovery Today. 2005;10(9):617–25.

    Article  CAS  Google Scholar 

  • Takasugi N, et al. The emerging role of electrophiles as a key regulator for endoplasmic reticulum (ER) stress. Int J Mol Sci. 2019;20(7).

  • Tao T, et al. The PERK/Nrf2 pathway mediates endoplasmic reticulum stress-induced injury by upregulating endoplasmic reticulophagy in H9c2 cardiomyoblasts. Life Sci. 2019;237:116944.

    Article  CAS  Google Scholar 

  • Tesz GJ, et al. Tumor necrosis factor alpha (TNFalpha) stimulates Map4k4 expression through TNFalpha receptor 1 signaling to c-Jun and activating transcription factor 2. J Biol Chem. 2007;282(27):19302–12.

    Article  CAS  Google Scholar 

  • Thompson RA, et al. Reactive metabolites: current and emerging risk and hazard assessments. Chem Res Toxicol. 2016;29(4):505–33.

    Article  CAS  Google Scholar 

  • Tian Y, Zheng J. Chapter Six - metabolic activation and toxicities of bis-benzylisoquinoline alkaloids, in Advances in Molecular Toxicology, J.C. Fishbein and J.M. Heilman, Editors. 2017, Elsevier. p. 241-272.

  • Tomberg A, et al. Understanding P450-mediated bio-transformations into epoxide and phenolic metabolites. Angew Chem Int Ed Engl. 2015;54(46):13743–7.

    Article  CAS  Google Scholar 

  • Torres S, et al. Valproic acid and acetaminophen comedication causes liver injury by synergistically inducing endoplasmic reticulum stress through GSH depletion. Hepatology. 2018;68:203a–4a.

    Google Scholar 

  • Tu W, et al. The anti-inflammatory and anti-oxidant mechanisms of the Keap1/Nrf2/ARE signaling pathway in chronic diseases. Aging Dis. 2019;10(3):637–51.

    Article  Google Scholar 

  • Turjanski AG, Vaque JP, Gutkind JS. MAP kinases and the control of nuclear events. Oncogene. 2007;26(22):3240–53.

    Article  CAS  Google Scholar 

  • Uzi D, et al. CHOP is a critical regulator of acetaminophen-induced hepatotoxicity. J Hepatol. 2013;59(3):495–503.

    Article  CAS  Google Scholar 

  • Valko M, et al. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39(1):44–84.

    Article  CAS  Google Scholar 

  • Vevea JD, et al. Role for lipid droplet biogenesis and microlipophagy in adaptation to lipid imbalance in yeast. Dev Cell. 2015;35(5):584–99.

    Article  CAS  Google Scholar 

  • Vukic V, et al. Expression of inflammatory genes induced by beta-amyloid peptides in human brain endothelial cells and in Alzheimer's brain is mediated by the JNK-AP1 signaling pathway. Neurobiol Dis. 2009;34(1):95–106.

    Article  CAS  Google Scholar 

  • Wang X, et al. Mechanism of arylating quinone toxicity involving Michael adduct formation and induction of endoplasmic reticulum stress. Proc Natl Acad Sci U S A. 2006;103(10):3604–9.

    Article  CAS  Google Scholar 

  • Xu J, Taubert S. Beyond proteostasis: lipid metabolism as a new player in ER homeostasis. Metabolites. 2021;11:1.

    Article  Google Scholar 

  • Yan M, et al. Enhancement of TEX264-mediated ER-phagy contributes to the therapeutic effect of glycycoumarin against APA hepatotoxicity in mice. Biomedicines. 2021;9(8).

  • Yoshida H, et al. pXBP1(U) encoded in XBP1 pre-mRNA negatively regulates unfolded protein response activator pXBP1(S) in mammalian ER stress response. J Cell Biol. 2006;172(4):565–75.

    Article  CAS  Google Scholar 

  • Yun SY, et al. Comparison of three human liver cell lines for in vitro drug-induced liver injury assessment: Huh7, HepaRG, and stem cell-derived hepatocytes. Mol Cell Toxicol. 2019;15(3):271–85.

    Article  CAS  Google Scholar 

  • Zhang K, Kaufman RJ. The unfolded protein response: a stress signaling pathway critical for health and disease. Neurology. 2006;66(2 Suppl 1):S102–9.

    Article  CAS  Google Scholar 

  • Zhang G, et al. PERK regulates Nrf2/ARE antioxidant pathway against dibutyl phthalate-induced mitochondrial damage and apoptosis dependent of reactive oxygen species in mouse spermatocyte-derived cells. Toxicol Lett. 2019;308:24–33.

    Article  CAS  Google Scholar 

  • Zhou L, et al. The covalent binding of [14C]acetaminophen to mouse hepatic microsomal proteins: the specific binding to calreticulin and the two forms of the thiol:protein disulfide oxidoreductases. Chem Res Toxicol. 1996;9(7):1176–82.

    Article  CAS  Google Scholar 

  • Zhou S, et al. Drug bioactivation, covalent binding to target proteins and toxicity relevance. Drug Metab Rev. 2005;37(1):41–213.

    Article  CAS  Google Scholar 

  • Zhou X, et al. Effect of fluoride on PERK-Nrf2 signaling pathway in mouse ameloblasts. Hum Exp Toxicol. 2019;38(7):833–45.

    Article  CAS  Google Scholar 

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Acknowledgements

The authors would like to thank the Ministry of Finance and the Ministry of Education of PRC (People’s Republic of China) for BUCM (Beijing University of Chinese Medicine).

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Funding

This work was supported by the Beijing Natural Science Foundation [7202111] and the National Science and Technology Major Project [2018ZX10101001-005-003].

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Authors and Affiliations

  1. School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China

    Qingcai Huang, Youwen Chen, Zhengjia Zhang, Zeyu Xue, Zhenglai Hua, Xinyi Luo, Yang Li & Yuanyan Liu

  2. Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China

    Cheng Lu

  3. School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong, China

    Aiping Lu

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  1. Qingcai Huang
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  4. Zeyu Xue
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  5. Zhenglai Hua
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  7. Yang Li
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  9. Aiping Lu
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  10. Yuanyan Liu
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Contributions

Yuanyan Liu, Cheng Lu, and Aiping Lu conceptualized the review; Qingcai Huang, Youwen Chen, Zhengjia Zhang, Zeyu Xue, Zhenglai Hua, Xinyi Luo, and Yang Li produced initial drafts of the manuscript and drew the figures; Yuanyan Liu, Cheng Lu and Aiping Lu critically revised the work. All authors approved the final manuscript and agreed with its publication.

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Correspondence to Yuanyan Liu.

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Highlights

• ER is the site of drug metabolism and is one of the most vulnerable targets to reactive metabolites.

• Reactive metabolites can cause the accumulation of unfolded or misfolded proteins in the ER and finally result in ER stress.

• Reactive metabolites trigger ER toxicity and may be partly restored by UPR-mediated adaptive pathways but mostly lead to cell death and inflammatory cascade.

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Huang, Q., Chen, Y., Zhang, Z. et al. The endoplasmic reticulum participated in drug metabolic toxicity. Cell Biol Toxicol 38, 945–961 (2022). https://doi.org/10.1007/s10565-021-09689-8

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  • DOI: https://doi.org/10.1007/s10565-021-09689-8

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