Abstract
Humans are exposed to hydroquinone (HQ) via diet, smoking, occupation, and even via inhalation of polluted air. Given its preferential distribution in kidney and liver, the impact of biotransformation on the nephrotoxicity and hepatotoxicity of HQ was evaluated. Indeed, HQ and its metabolites, benzoquinone, and quinone–thioethers (50, 100, 200, and 400 μM) all induced ROS-dependent cell death in both HK-2, a human kidney proximal epithelial cell line, and THLE-2, a human liver epithelial cell line, in a concentration-dependent manner. For a deeper insight into the biological mechanism of ROS stimulation, the bioinformatics database was reviewed. Intriguingly, 163 proteins were currently reported to form co-crystal complex with benzoquinone analogs, a large proportion of which are closely related to ROS generation. After a thorough assessment of the interaction affinity and binding energy, three key mitochondrial proteins that are particularly involved in electric transport, namely, cytochrome BC1, succinate dehydrogenase, and sulfide:quinone oxidoreductase, were highlighted for further verification. Their binding affinity and the action pattern were explored and validated by molecular docking and molecular dynamics simulations. Remarkably, quinone–thioether metabolites of HQ afforded high affinity to the above proteins that purportedly cause a surge in the generation of ROS. Therefore, HQ can be further converted into quinone–thioethers, which on one hand can function as substrates for redox cycling, and on the other hand may afford high affinity with key proteins evolved in mitochondrial electron transport system, leading to a vicious cycle of ROS generation. The combined data provide a prospective insight into the mechanisms of ROS motivation, expanding HQ-mediated toxicology profiles.
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References
Baratta M, Miretti S, Macchi E, Accornero P, Martignani E (2018) Mammary stem cells in domestic animals: the role of ROS. Antioxidants (Basel) 8(1):6. https://doi.org/10.3390/antiox8010006
Bauza A, Quinonero D, Deya PM, Frontera A (2013) On the importance of anion-pi interactions in the mechanism of sulfide:quinone oxidoreductase. Chem Asian J 8(11):2708–2713. https://doi.org/10.1002/asia.201300786
Bonke E, Zwicker K, Drose S (2015) Manganese ions induce H2O2 generation at the ubiquinone binding site of mitochondrial complex II. Arch Biochem Biophys 580:75–83. https://doi.org/10.1016/j.abb.2015.06.011
Cheeseright TJ, Mackey MD, Scoffin RA (2011) High content pharmacophores from molecular fields: a biologically relevant method for comparing and understanding ligands. Curr Comput Aided Drug Des 7(3):190–205
Dhingra R, Kirshenbaum LA (2015) Succinate dehydrogenase/complex II activity obligatorily links mitochondrial reserve respiratory capacity to cell survival in cardiac myocytes. Cell Death Dis 6:e1956. https://doi.org/10.1038/cddis.2015.310
Divincenzo GD, Hamilton ML, Reynolds RC, Ziegler DA (1984) Metabolic fate and disposition of [14C]hydroquinone given orally to Sprague-Dawley rats. Toxicology 33(1):9–18
do Ceu Silva M, Gaspar J, Duarte Silva I, Leao D, Rueff J (2003) Mechanisms of induction of chromosomal aberrations by hydroquinone in V79 cells. Mutagenesis 18(6):491–496
Dong J, Ramachandiran S, Tikoo K, Jia Z, Lau SS, Monks TJ (2004) EGFR-independent activation of p38 MAPK and EGFR-dependent activation of ERK1/2 are required for ROS-induced renal cell death. Am J Physiol Renal Physiol 287(5):F1049–F1058. https://doi.org/10.1152/ajprenal.00132.2004
Elfawy HA, Das B (2018) Crosstalk between mitochondrial dysfunction, oxidative stress, and age related neurodegenerative disease: etiologies and therapeutic strategies. Life Sci 218:165–184. https://doi.org/10.1016/j.lfs.2018.12.029
Fisher AA, Labenski MT, Malladi S et al (2007) Quinone electrophiles selectively adduct “electrophile binding motifs” within cytochrome c. Biochemistry 46(39):11090–11100. https://doi.org/10.1021/bi700613w
Josch C, Sies H, Akerboom TP (1998) Hepatic mercapturic acid formation: involvement of cytosolic cysteinylglycine S-conjugate dipeptidase activity. Biochem Pharmacol 56(6):763–771
Kerzic PJ, Liu WS, Pan MT et al (2010) Analysis of hydroquinone and catechol in peripheral blood of benzene-exposed workers. Chem Biol Interact 184(1–2):182–188. https://doi.org/10.1016/j.cbi.2009.12.010
Ketterer B (1988) Protective role of glutathione and glutathione transferases in mutagenesis and carcinogenesis. Mutat Res 202(2):343–361
Kleiner HE, Jones TW, Monks TJ, Lau SS (1998) Immunochemical analysis of quinol-thioether-derived covalent protein adducts in rodent species sensitive and resistant to quinol-thioether-mediated nephrotoxicity. Chem Res Toxicol 11(11):1291–1300. https://doi.org/10.1021/tx9801357
Lau SS, Monks TJ (1987) Co-oxidation of 2-bromohydroquinone by renal prostaglandin synthase. Modulation of prostaglandin synthesis by 2-bromohydroquinone and glutathione. Drug Metab Dispos 15(6):801–807
Lau SS, Hill BA, Highet RJ, Monks TJ (1988a) Sequential oxidation and glutathione addition to 1,4-benzoquinone: correlation of toxicity with increased glutathione substitution. Mol Pharmacol 34(6):829–836
Lau SS, McMenamin MG, Monks TJ (1988b) Differential uptake of isomeric 2-bromohydroquinone-glutathione conjugates into kidney slices. Biochem Biophys Res Commun 152(1):223–230
Lau SS, Monks TJ, Everitt JI, Kleymenova E, Walker CL (2001) Carcinogenicity of a nephrotoxic metabolite of the “nongenotoxic” carcinogen hydroquinone. Chem Res Toxicol 14(1):25–33
Levitt J (2007) The safety of hydroquinone: a dermatologist’s response to the 2006 federal register. J Am Acad Dermatol 57(5):854–872. https://doi.org/10.1016/j.jaad.2007.02.020
Li RJ, Wang J, Xu Z et al (2014) Computational insight into p21-activated kinase 4 inhibition: a combined ligand- and structure-based approach. ChemMedChem 9(5):1012–1022. https://doi.org/10.1002/cmdc.201400016
Li RJ, Wang YL, Wang QH, Wang J, Cheng MS (2015) In silico design of human IMPDH inhibitors using pharmacophore mapping and molecular docking approaches. Comput Math Methods Med 2015:418767. https://doi.org/10.1155/2015/418767
Li W, Liu X, Muhammad S, Shi J, Meng Y, Wang J (2018) Computational investigation of TGF-beta receptor inhibitors for treatment of idiopathic pulmonary fibrosis: field-based QSAR model and molecular dynamics simulation. Comput Biol Chem 76:139–150. https://doi.org/10.1016/j.compbiolchem.2018.07.002
Liu Z, Ren Z, Zhang J et al (2018) Role of ROS and nutritional antioxidants in human diseases. Front Physiol 9:477. https://doi.org/10.3389/fphys.2018.00477
Makeneni S, Thieker DF, Woods RJ (2018) Applying pose clustering and MD simulations to eliminate false positives in molecular docking. J Chem Inf Model 58(3):605–614. https://doi.org/10.1021/acs.jcim.7b00588
Marcia M, Ermler U, Peng G, Michel H (2009) The structure of Aquifex aeolicus sulfide:quinone oxidoreductase, a basis to understand sulfide detoxification and respiration. Proc Natl Acad Sci USA 106(24):9625–9630. https://doi.org/10.1073/pnas.0904165106
Monks TJ, Lau SS (1994) Glutathione conjugation as a mechanism for the transport of reactive metabolites. Adv Pharmacol 27:183–210
Monks TJ, Lau SS (1997) Biological reactivity of polyphenolic-glutathione conjugates. Chem Res Toxicol 10(12):1296–1313. https://doi.org/10.1021/tx9700937
Monks TJ, Hanzlik RP, Cohen GM, Ross D, Graham DG (1992) Quinone chemistry and toxicity. Toxicol Appl Pharmacol 112(1):2–16
Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65(1–2):55–63
Niculescu R, Renz JF, Kalf GF (1996) Benzene-induced bone marrow cell depression caused by inhibition of the conversion of pre-interleukins-1alpha and -1beta to active cytokines by hydroquinone, a biological reactive metabolite of benzene. Adv Exp Med Biol 387:329–337
Noha SM, Schmidhammer H, Spetea M (2017) molecular docking, molecular dynamics, and structure-activity relationship explorations of 14-oxygenated N-methylmorphinan-6-ones as potent mu-opioid receptor agonists. ACS Chem Neurosci 8(6):1327–1337. https://doi.org/10.1021/acschemneuro.6b00460
North M, Tandon VJ, Thomas R et al (2011) Genome-wide functional profiling reveals genes required for tolerance to benzene metabolites in yeast. PLoS One 6(8):e24205. https://doi.org/10.1371/journal.pone.0024205
North M, Shuga J, Fromowitz M et al (2014) Modulation of Ras signaling alters the toxicity of hydroquinone, a benzene metabolite and component of cigarette smoke. BMC Cancer 14:6. https://doi.org/10.1186/1471-2407-14-6
Obiol-Pardo C, Rubio-Martinez J (2007) Comparative evaluation of MMPBSA and XSCORE to compute binding free energy in XIAP-peptide complexes. J Chem Inf Model 47(1):134–142. https://doi.org/10.1021/ci600412z
Quinlan CL, Orr AL, Perevoshchikova IV, Treberg JR, Ackrell BA, Brand MD (2012) Mitochondrial complex II can generate reactive oxygen species at high rates in both the forward and reverse reactions. J Biol Chem 287(32):27255–27264. https://doi.org/10.1074/jbc.M112.374629
Shibata MA, Hirose M, Tanaka H, Asakawa E, Shirai T, Ito N (1991) Induction of renal cell tumors in rats and mice, and enhancement of hepatocellular tumor development in mice after long-term hydroquinone treatment. Jpn J Cancer Res 82(11):1211–1219
Subrahmanyam VV, Doane-Setzer P, Steinmetz KL, Ross D, Smith MT (1990) Phenol-induced stimulation of hydroquinone bioactivation in mouse bone marrow in vivo: possible implications in benzene myelotoxicity. Toxicology 62(1):107–116
Vinogradov AD, Grivennikova VG (2016) Oxidation of NADH and ROS production by respiratory complex I. Biochim Biophys Acta 1857(7):863–871. https://doi.org/10.1016/j.bbabio.2015.11.004
Wang M, Li W, Wang Y, Song Y, Wang J, Cheng M (2018) In silico insight into voltage-gated sodium channel 1.7 inhibition for anti-pain drug discovery. J Mol Graph Model 84:18–28. https://doi.org/10.1016/j.jmgm.2018.05.006
Yankovskaya V, Horsefield R, Tornroth S et al (2003) Architecture of succinate dehydrogenase and reactive oxygen species generation. Science 299(5607):700–704. https://doi.org/10.1126/science.1079605
Zhang Z, Huang L, Shulmeister VM et al (1998) Electron transfer by domain movement in cytochrome bc1. Nature 392(6677):677–684. https://doi.org/10.1038/33612
Zhang F, Lau SS, Monks TJ (2011) The cytoprotective effect of N-acetyl-l-cysteine against ROS-induced cytotoxicity is independent of its ability to enhance glutathione synthesis. Toxicol Sci 120(1):87–97. https://doi.org/10.1093/toxsci/kfq364
Zhang F, Xie R, Munoz FM, Lau SS, Monks TJ (2014) PARP-1 hyperactivation and reciprocal elevations in intracellular Ca2+ during ROS-induced nonapoptotic cell death. Toxicol Sci 140(1):118–134. https://doi.org/10.1093/toxsci/kfu073
Zhu XL, Xiong L, Li H, Song XY, Liu JJ, Yang GF (2014) Computational and experimental insight into the molecular mechanism of carboxamide inhibitors of succinate-ubquinone oxidoreductase. ChemMedChem 9(7):1512–1521. https://doi.org/10.1002/cmdc.201300456
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This work was supported by the National Natural Science Foundation of China (21507093).
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Mao, J., Dai, W., Zhang, S. et al. Quinone–thioether metabolites of hydroquinone play a dual role in promoting a vicious cycle of ROS generation: in vitro and in silico insights. Arch Toxicol 93, 1297–1309 (2019). https://doi.org/10.1007/s00204-019-02443-4
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DOI: https://doi.org/10.1007/s00204-019-02443-4