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Quinone–thioether metabolites of hydroquinone play a dual role in promoting a vicious cycle of ROS generation: in vitro and in silico insights

  • Jianping Mao
  • Wenbin Dai
  • Shuya Zhang
  • Lanlan Sun
  • Hanxun Wang
  • Yinli Gao
  • Jian WangEmail author
  • Fengjiao ZhangEmail author
Molecular Toxicology

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.

Keywords

Hydroquinone Docking Molecular dynamics simulations ROS Quinone–thioether 

Notes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (21507093).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The manuscript does not contain clinical studies or patient data.

Supplementary material

204_2019_2443_MOESM1_ESM.docx (3.5 mb)
Supplementary material 1 (DOCX 3597 kb)

References

  1. 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 CrossRefGoogle Scholar
  2. 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 CrossRefGoogle Scholar
  3. 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 CrossRefGoogle Scholar
  4. 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):190–205CrossRefGoogle Scholar
  5. 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 CrossRefGoogle Scholar
  6. 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):9–18CrossRefGoogle Scholar
  7. 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):491–496CrossRefGoogle Scholar
  8. 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 CrossRefGoogle Scholar
  9. 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 CrossRefGoogle Scholar
  10. 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 CrossRefGoogle Scholar
  11. Josch C, Sies H, Akerboom TP (1998) Hepatic mercapturic acid formation: involvement of cytosolic cysteinylglycine S-conjugate dipeptidase activity. Biochem Pharmacol 56(6):763–771CrossRefGoogle Scholar
  12. 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 CrossRefGoogle Scholar
  13. Ketterer B (1988) Protective role of glutathione and glutathione transferases in mutagenesis and carcinogenesis. Mutat Res 202(2):343–361CrossRefGoogle Scholar
  14. 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 CrossRefGoogle Scholar
  15. 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):801–807Google Scholar
  16. 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):829–836Google Scholar
  17. Lau SS, McMenamin MG, Monks TJ (1988b) Differential uptake of isomeric 2-bromohydroquinone-glutathione conjugates into kidney slices. Biochem Biophys Res Commun 152(1):223–230CrossRefGoogle Scholar
  18. 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):25–33CrossRefGoogle Scholar
  19. 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 CrossRefGoogle Scholar
  20. 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 CrossRefGoogle Scholar
  21. 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 Google Scholar
  22. 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 CrossRefGoogle Scholar
  23. 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 CrossRefGoogle Scholar
  24. 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 CrossRefGoogle Scholar
  25. 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 CrossRefGoogle Scholar
  26. Monks TJ, Lau SS (1994) Glutathione conjugation as a mechanism for the transport of reactive metabolites. Adv Pharmacol 27:183–210CrossRefGoogle Scholar
  27. Monks TJ, Lau SS (1997) Biological reactivity of polyphenolic-glutathione conjugates. Chem Res Toxicol 10(12):1296–1313.  https://doi.org/10.1021/tx9700937 CrossRefGoogle Scholar
  28. Monks TJ, Hanzlik RP, Cohen GM, Ross D, Graham DG (1992) Quinone chemistry and toxicity. Toxicol Appl Pharmacol 112(1):2–16CrossRefGoogle Scholar
  29. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65(1–2):55–63CrossRefGoogle Scholar
  30. 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 387:329–337CrossRefGoogle Scholar
  31. 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 CrossRefGoogle Scholar
  32. 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 CrossRefGoogle Scholar
  33. 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 CrossRefGoogle Scholar
  34. 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 CrossRefGoogle Scholar
  35. 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 CrossRefGoogle Scholar
  36. 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):1211–1219CrossRefGoogle Scholar
  37. 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):107–116CrossRefGoogle Scholar
  38. 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 CrossRefGoogle Scholar
  39. 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 CrossRefGoogle Scholar
  40. 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 CrossRefGoogle Scholar
  41. 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 CrossRefGoogle Scholar
  42. 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 CrossRefGoogle Scholar
  43. 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 CrossRefGoogle Scholar
  44. 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 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Wuya College of InnovationShenyang Pharmaceutical UniversityShenyangChina
  2. 2.Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of EducationShenyang Pharmaceutical UniversityShenyangChina

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