Toluenin Nitrik Oksit Üretimine Etkisinin ve Resveratrolün Koruyucu Özelliklerinin Araştırılması

Amaç: Organik çözücü olarak en çok tercih edilen Toluendir. Toluene uzun süre maruz kalmak ciddi sağlık sorunlarına neden olur. Uluslararası Kanser Araştırmaları Birliği (IACR), tolüeni "insanlar için muhtemelen kanserojen" (Grup 2B) olarak sınıflandırmıştır. Bu sınıflandırma, toluenin potansiyel kanserojen etkilere sahip olabileceğini belirtir. Toluene maruz kalma, reaktif nitrojen türlerinin ve reaktif oksijen türlerinin oluşumuyla bağlantılı olup, doğrudan doku hasarına ve çeşitli antioksidan sistemlerin değişmesine neden olur. Polifenol yapısında olan resveratrol, bitkilerde önemli etkilere sahip bir moleküldür. İnsanlarda da olumlu etkilere sahip olduğu bilinmektedir. Bu çalışmada, kardiyovasküler, nörolojik, immünolojik ve diğer birçok sistemde biyolojik düzenleyici olarak önemli bir role sahip olan nitrik oksit üretimine toluene maruz kalmanın etkisi ve resveratrolün koruyucu özellikleri araştırılmıştır. Yöntem: Tolüenin 900mg/kg dozu erkek sıçanlara (250-350gr Wistar-Albino) intraperitoneal yolla uygulanırken resveratrol 5, 10 ve 20mg/kg dozları aynı yolla altı gün boyunca uygulanmıştır. Karaciğer dokusunda ve serumda nitrik oksit seviyeleri ve nitrik oksit sentaz aktiviteleri araştırılmıştır. Bulgular: Veriler, karaciğer dokusunda ve serumda nitrik oksit seviyesinin arttığını ve toluen uygulamasını takiben yüksek nitrik oksit sentaz aktivitesini gösterdi. Resveratrolün çeşitli dozlarının uygulanmasından sonra karaciğerde nitrik oksit seviyelerinde ve nitrik oksit sentaz aktivitesinde önemli azalmalar gözlendi. Sonuçlar: Sonuçlarımız yüksek dozda toluenin nitrik oksit üretimini tetiklediğini, resveratrolün ise koruyucu özelliklere sahip olduğunu gösterdi.

Anahtar Kelimeler:

Toluene, resveratrol, nitric oxide, nitric oxide synthase

Investigation of the Effect of Toluene on Nitric Oxide Production and Protective Properties of Resveratrol

Aim: Toluene is the most preferred organic solvent. Prolonged exposure to toluene, causes serious health problems. The International Agency for Research on Cancer (IARC) has classified toluene as "possibly carcinogenic to humans" (Group 2B). This classification states that toluene may have potential carcinogenic effects. Toluene exposure has been linked to the formation of reactive nitrogen species and reactive oxygen species, resulting in direct tissue damage and alteration of various antioxidant systems. Resveratrol, which has a polyphenol structure, is a molecule that has important effects on plants. It is known to have positive effects on humans as well. In this study, the effect of exposure to toluene on nitric oxide production, which has an important role as a biological regulator in cardiovascular, neurological, immunological and many other systems, and the protective properties of resveratrol were investigated. Materials and Methods While 900mg/kg dose of toluene was administered intraperitoneally to male rats (250-350gr Wistar-Albino), 5, 10 and 20mg/kg doses of resveratrol were administered the same way for six days. Nitric oxide levels and Nitric oxide synthase activities were investigated in liver tissue and serum. Finding: The data showed an increased nitric oxide level in the liver tissue and serum and a high nitric oxide synthase activity following toluene administration. Significant reductions in nitric oxide levels and nitric oxide synthase activity in the liver were observed after the administration of various dosages of resveratrol. Results: Our results suggested that high doses of toluene induce nitric oxide production, whereas resveratrol possesses protective properties.

Keywords:

Toluene, resveratrol, nitric oxide, nitric oxide synthase,

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Agency for Toxic Substances and Disease Registry (2017). Toxicological profile for toluene. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service. https://wwwn.cdc.gov/TSP/ToxProfiles/ToxProfiles.aspx?id=161&tid=29
Balster, R.L., Cruz, S.L., Howard, M.O., Dell, C.A and Cottler, L.B. (2009). Classification of abused inhalants. Addiction, 104: 878–882, doi:10.1111/j.1360-0443.2008.02494.x
Cai, H., Scott, E., Kholghi, A., Andreadi, C,. Rufini, A., Karmokar, A., … Brown, K. (2015). Cancer chemoprevention: evidence of a nonlinear dose response for the protective effects of resveratrol in humans and mice. Science translational medicine, 29(7) (298)ra117, doi:10.1126/scitranslmed.aaa7619
Chitarrini, G., Zulini, L., Masuero, D and Vrhovsek U. (2017). Lipid, phenol and carotenoid changes in “Bianca” grapevine leaves after mechanical wounding: a case study, Protoplasma, 254(6), 2095–2106, doi:10.1007/s00709-017-1100-5
Choi, G. S., Trinh, H. K. T., Yang, E. M., Ye, Y. M , Shin, Y. S., Kim, S. H. and Park, H. S. (2018). Role of clusterin/progranulin in toluene diisocyanate-induced occupational asthma. Experimental and Molecular Medicine, 50, 1-10, doi:10.1038/s12276-018-0085-2
Das, S. and Das, D. K. (2007). Anti-inflammatory responses of resveratrol. Inflammation and Allergy - Drug Targets, 6(3), 168–173, doi:10.2174/187152807781696464
Elabscience Biotechnology Inc. (2018). Nitric Oxide (NO) Colorimetric Assay Kit. All Rights Reserved 8th Edition. https://file.elabscience.com/Manual/biochemical_kits/E-BC-K035-S-Elabscience.pdf
Espinoza, J. L., Kurokawa, Y. and Takami, A, (2019). Rationale for assessing the therapeutic potential of resveratrol in haematological malignancies. Blood Reviews. 33, 43-52, doi:10.1016/j.blre.2018.07.001
Fang, W., Jiang, J., Su, L., Shu, T., Liu, H., Lai, S., … Wang, J. (2021). The role of NO in COVID-19 and potential therapeutic strategies. Free Radical Biology and Medicine 163, 153–162, doi:10.1016/j.freeradbiomed.2020.12.008
Gotohda, T., Nishimura, A. and Morita, K. (2009). Immunohistochemical studies on early stage of hepatic damage induced by subacute inhalation of toluene vapor in rats. Journal of Applied Toxicology, 29(6), 505–509, doi:org/10.1002/jat.1435
Gupta, S. C., Kannappan, R., Reuter, S., Kim, J. H. and Aggarwal, B. (2011). Chemosensitization of tumors by resveratrol. Annals of The New York Academy of Sciences, 1215, 150–160, doi:10.1111/j.1749-6632.2010.05852.x
Hasan, M. M. and Bae, H. (2017). An overview of stress-induced resveratrol synthesis in grapes: Perspectives for resveratrol-enriched grape products. Molecules, 22(2). 294, doi:10.3390/molecules22020294
Hong, G, Zhang, B. and Harbrech,. B. G. (2010). Cyclic AMP inhibits IL-1beta plus IFN gamma-induced NF-kappaB translocation in hepatocytes by a PKA independent mechanism. Journal of Surgical Research,159(1):565–571, doi:10.1016/j.jss.2008.12.018
Huffman, L. J., Judy, D.J., Frazer, D., Shapiro, R. E., Castranova, V., Billie, M. and Dedhia, H. V. (1997). Inhalation of toluene diisocyanate is associated with increased production of nitric oxide by rat Broncho alveolar lavage cells. Toxicology and Applied Pharmacology, 145(1), 61–67, doi:10.1006/taap.1997.8162
Kim, K. W., Won, Y.L. and Ko, K. S. (2015). Ethnic differences in the metabolism of toluene: Comparisons between Korean and foreign workers exposed to toluene. Toxicological Research, 31(1), 25–32, doi:10.5487/TR.2015.31.1.025
Kimbrough, C. W., Lakshmanan, J., Matheson, P. J., Woeste, M., Gentile, A., Benns, M. V., … Harbrecht, B. G. (2015). Resveratrol Decreases Nitric Oxide Production by hepatocytes during inflammation. Surgery, 158(4), 1095–1101, doi:10.1016/j.surg.2015.07.012.
Kurutas, E. B. (2016). The importance of antioxidants which play the role in cellular response against oxidative/nitrosative stress: current state. Nutrition Journal, 15(1), 71, doi:10.1186/s12937-016-0186-5
Li, Y. R., Li, S. and Lin, C. C. (2018). Effect of resveratrol and pterostilbene on aging and longevity. BioFactors, 44(1), 69–82, doi:10.1002/biof.1400
Lu, D. L., Ding, D., Yan, W. and Li, R.W. (2013). Influence of glucuronidation and reduction modifications of resveratrol on its biological activities. Chembiochem 14(9), 1094–1104, doi:10.1002/cbic.201300080
Manna, S. K., Mukhopadhyay, A. and Aggarwal, B. B. (2000). Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kB, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. The Journal of Immunology, 164(12), 6509–6519, doi:10.4049/jimmunol.164.12.6509
Mattia, C. J., Ali, S. F. and Bondy, S. C. (1993). Toluene-induced oxidative stress in several brain regions and other organs. Molecular and Chemical Neuropathology, 18, 313–328, https://link.springer.com/article/10.1007/BF03160122
McGill, M. R., Du, K., Weemhoff, J. L. and Jaeschke, H. (2015). Critical review of resveratrol in xenobiotic-induced hepatotoxicity. Food and Chemical Toxicolology, 86: 309–318, doi:10.1016/j.fct.2015.11.003
Miki, H., Tokuhara, K., Oishi, M., Nakatake, R., Tanaka, Y., Kaibori, M… Kon, M. (2016). Japanese kampo saireito has a liver-protective effect through the inhibition of inducible nitric oxide synthase induction in primary cultured rat hepatocytes. Journal of Parenteral and Enteral Nutrition, 40(7), 1033-1041, doi:10.1177/0148607115575035
Navarro-Cruz, A. R, Ayala, R. R., Velasso, C. O., Brambila, E., Sosa, R. A., Fernández, S. P.… Alonso, P. A. (2017). Effect of Chronic Administration of Resveratrol on Cognitive Performance during Aging Process in Rats. Oxidative Medicine and Cellular Longevity, doi:10.1155/2017/8510761
Pelletti, G., Rossi, F., Garagnani, M. and Barone, R. (2018). Medico-legal implications of toluene abuse and toxicity. Review of cases along with blood concentrations. Legal Medicine, 34, 48-57, doi:10.1016/j.legalmed.2018.08.008
Pradhan, A. A., Bertels, Z. and Akerman, S. (2018). Targeted nitric oxide synthase inhibitors for migraine. Neurotherapeutics, 15(2), 391-401, doi:10.1007/s13311-018-0614-7
Truong, V. L., Jun, M. and Jeong, W. S. (2018). Role of resveratrol in regulation of cellular defense systems against oxidative stress. BioFactors 44(1), 36-49, doi:10.1002/biof.1399
Tsai, S. H., Lin-Shiau, S. Y. and Lin, J. K. (1999). Suppression of nitric oxide synthase and the down-regulation of the activation of NFκB in macrophages by resveratrol. British Journal of Pharmacology, 126(3), 673–680, doi:10.1038/sj.bjp.0702357
Villaflores, O. B., Chen, Y. J., Chen, C. P., Yeh, J. M. and Wu, T. Y. (2012). Curcuminoids and resveratrol as anti-Alzheimer agents, Taiwanese Journal of Obstetrics and Gynecolog, 51(4), 515-525, doi:10.1016/j.tjog.2012.09.005
Wallerath, T., Deckert, G., Ternes, T., Anderson, H., Li, H., Witte, K. and Förstermann, U. (2002). Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase. Circulation 106(13), 1652–1658, doi: 10.1161/01.cir.0000029925.18593.5c.
Wallerath, T., Poleo, D., Li, H. and Förstermann, U. (2003). Red wine increases the expression of human endothelial nitric oxide synthase: A mechanism that may contribute to its beneficial cardiovascular effects. Journal of the American College of Cardiology, 41(3), 471–478, doi:10.1016/s0735-1097(02)02826-7.
Wallerath, T., Li, H., Godtel-Ambrust, U. and Schwarz, P. M. (2005). A blend of polyphenolic compounds explains the stimulatory effect of red wine on human endothelial NO synthase. Nitric Oxide 12(2), 97-104, doi:10.1016/j.niox.2004.12.004
Xia, N., Daiber, A., Förstermann, U. and Li, H. (2017). Antioxidant effects of resveratrol in the cardiovascular system. British Journal of Pharmacology, 174(12), 1633-1646, doi:10.1111/bph.13492
Yeung, F., Hoberg, J. E., Ramsey, C. S., Keller, M. D., Joney, D. R., Frye, R. A. and Mayo, M. W. (2004). Modulation of NF-κB-dependent transcription and cell survival by the SIRT1 deacetylase. The EMBO Journal, 23(12), 2369–2380, doi:10.1038/sj.emboj.7600244
Yu, X., Ge, L., Niu, L., Lian, X., Ma, H. and Pang, L. (2018). The dual role of inducible nitric oxide synthase in myocardial ischemia/reperfusion injury: Friend or foe? Oxidative Medicine and Cellular Longevity, doi:org/10.1155/2018/8364848
Zhang, B., Perpetua, M., Fulmer, M. and Harbrecht, B. G. (2004). JNK signaling involved in the effects of cyclic AMP on IL-1beta plus IFN gamma-induced inducible nitric oxide synthase expression in hepatocytes. Cellular Signalling, 16(7), 837–846, doi:10.1016/j.cellsig.2004.01.001.