Abstract
Neurons and glia are highly susceptible to reactive oxygen species that play a key role in various neurodegenerative diseases. Menadione, a synthetic derivative of vitamin K, induces reactive oxygen generation. Quercetin one of the most ubiquitous bioflavonoids in food of plant origin, has strong antioxidant activities on different cell types, however recent studies demonstrated that it has also prooxidant and cytotoxic potentials. We examined the action of pre- and co-treatment of quercetin on menadione induced glial toxicity. The primary mixed glial cells obtained from 1 to 3 day old rat brain were pretreated with 10, 25, 100 or 250 μM quercetin for 1 h, washed out and 10, 25, 50, 75 or 100 μM menadione was added for 6 h. The other group of cells was treated with respective doses of quercetin combined simultaneously with the same doses of menadione for 6 h. The cells were washed and incubated for additional 24 h for recovery period and the viability was measured by using MTT assay. Menadione was dose-dependently toxic to glia cells and pretreatment with respective quercetin doses for 1 h could not eliminate this toxicity. Although 10 and 25 μM quercetin combined with 10 and 25 μM menadione could not change, 100 and 250 μM quercetin together with 10 or 25 μM menadione for 6 h increased further the menadione induced toxicity. We conclude that when combined with menadione, quercetin at high doses could be toxic to primary rat glia cells in culture.
Similar content being viewed by others
References
Abe K, Saito H (1996) Menadione toxicity in cultured rat cortical astrocytes. Jpn J Pharmacol 72:299–306. doi:10.1254/jjp.72.299
Aherne SA, O’Brien NM (1999) Protection by the flavonoids myricetin, quercetin, and rutin against hydrogen peroxide-induced DNA damage in Caco-2 and Hep G2 cells. Nutr Cancer 34:160–166. doi:10.1207/S15327914NC3402_6
Aherne SA, O’Brien NM (2000) Mechanism of protection by the flavonoids, quercetin and rutin, against tert-butylhydroperoxide- and menadione-induced DNA single strand breaks in Caco-2 cells. Free Radic Biol Med 29:507–514. doi:10.1016/S0891-5849(00)00360-9
Awad HM, Boersma MG, Boeren S, Van Bladeren PJ, Vervoort J, Rietjens IMCM (2001) Structure—activity study on the quinone/quinone methide chemistry of flavonoids. Chem Res Toxicol 14:398–408. doi:10.1021/tx000216e
Awad HM, Boersma MG, Boeren S, Van Der Woude H, Van Zanden J, Van Bladeren PJ, Vervoort J, Rietjens IMCM (2002) Identification of o-quinone/quinone methide metabolites of quercetin in a cellular in vitro system. FEBS Lett 520:30–34. doi:10.1016/S0014-5793(02)02754-0
Bestwick CS, Milne L (2001) Quercetin modifies reactive oxygen levels but exerts only partial protection against oxidative stress within HL-60 cells. Biochim Biophys Acta 1528:49–59. doi:10.1016/S0304-4165(01)00167-2
Boots AW, Li H, Schins RPF, Duffin R, Heemskerk JWM, Bast A, Haenen GRMM (2007) The quercetin paradox. Toxicol Appl Pharmacol 222:89–96. doi:10.1016/j.taap.2007.04.004
Cafe C, Torri C, Bertorelli L, Tartara F, Tancioni F, Gaetani P, Baena RRY, Marzatio F (1995) Oxidative events in neuronal and glial cell-enriched fractions of rat cerebral cortex. Free Radic Biol Med 19:853–857. doi:10.1016/0891-5849(95)00086-D
Chiou TJ, Zhang J, Ferrans VJ, Tzeng WF (1997) Cardiac and renal toxicity of menadione in rat. Toxicology 124:193–202. doi:10.1016/S0300-483X(97)00162-5
Choi EJ, Chee KH, Lee BH (2003) Anti-and prooxidant effects of chronic quercetin administration in rats. Eur J Pharmacol 482:281–285. doi:10.1016/j.ejphar.2003.09.067
Floyd RA (1999) Antioxidants, oxidative stress, and degenerative neurological disorders. Proc Soc Exp Biol Med 222:236–245
Gitika B, Sai Ram M, Sharma K, Ilavazhagan G, Banerjee PK (2006) Quercetin protects C6 glial cells from oxidative stress induced by tertiary-butylhydroperoxide. Free Radic Biol Med 40:95–102. doi:10.1080/10715760500335447
Ha HJ, Kwon YS, Park SM, Shin T, Park JH, Kim HC, Kwon MS, Wie MB (2003) Quercetin attenuates oxygen-glucose deprivation- and excitotoxin-induced neurotoxicity in primary cortical cell cultures. Biol Pharm Bull 26:544–546. doi:10.1248/bpb.26.544
Harwood M, Danielewska-Nikiel B, Borzelleca JF, Flamm GW, Williams GM, Lines TC (2007) A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties. Food Chem Toxicol 45:2179–2205. doi:10.1016/j.fct.2007.05.015
Jagadeeswaran R, Thirunavukkarasu C, Gunasekaran P, Ramamurty N, Sakthisekaran D (2000) In vitro studies on the selective cytotoxic effect of crocetin and quercetin. Fitoterapia 71:395–399. doi:10.1016/S0367-326X(00)00138-6
Lamson DW, Brignall MS (2000) Antioxidants and cancer part 3: quercetin. Altern Med Rev 5:196–208
Lamson DW, Plaza SM (2003) The anticancer effects of vitamin K. Altern Med Rev 8:303–318
Lee JY, Bae ON, Chung SM, Lee MY, Chung JH (2001) Menadione induces endothelial dysfunction mediated by oxidative stress and arylation. Chem-Biol Interact 137:169–183. doi:10.1016/S0009-2797(01)00235-6
Lee JC, Kim J, Park JK, Chung GH, Jang YS (2003) The antioxidant, rather than prooxidant, activities of quercetin on normal cells: quercetin protects mouse thymocytes from glucose oxidase-mediated apoptosis. Exp Cell Res 291:386–397. doi:10.1016/S0014-4827(03)00410-5
Leuther S, Eckert A, Müller WE (2001) ROS generation, lipid peroxidation and antioxidant enzyme activities in the aging brain. J Neural Transm 108:955–967
Lopez MVN, Cuadrado MPG, Ruiz-Poveda OMP, Fresno AMVD, Accame MEC (2007) Neuroprotective effect of individual ginsenosides on astrocytes primary culture. Biochim Biophys Acta 1770:1308–1316. doi:10.1016/j.bbagen.2007.06.008
Matsuo M, Sasaki N, Saga K, Kaneko T (2005) Cytotoxicity of flavonoids toward cultured normal human cells. Biol Pharm Bull 28:253–259. doi:10.1248/bpb.28.253
Morrison H, Monte DI, Nordenskjöld M, Jernström B (1985) Induction of cell damage by menadione and benzo(a)pyrene-3, 6-quinone in cultures of adult rat hepatocytes and human fibroblasts. Toxicol Lett 28:37–47. doi:10.1016/0378-4274(85)90007-4
Mossmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Method 65:55–63. doi:10.1016/0022-1759(83)90303-4
Ngo EO, Sun TP, Chang JY, Wang CC, Chi KW, Cheng AL, Nutter LM (1999) Menadione-induced DNA damage in a human tumor cell line. Biochem Pharma 42:1961–1968
Park C, So HS, Shin CH, Baek SH, Moon BS, Shin SH, Lee HS, Lee DW, Park RK (2003) Quercetin protects the hydrogen peroxide-induced apoptosis via inhibition of mitochondrial dysfuntion in H9c2 cardiomyoblast cells. Biochem Pharmacol 66:1287–1295. doi:10.1016/S0006-2952(03)00478-7
Rouzaire-Dubois B, Gérard V, Dubois JM (1993) Involvement of K+ channels in the quercetin-induced inhibition of neuroblastoma cell growth. Pflugers Arch 423:202–205. doi:10.1007/BF00374395
Saito A, Sugisawa A, Umegaki K, Sunagawa H (2004) Protective effects of quercetin and its metabolites on H2O2-induced chromosomal damage to WIL2-NS cells. Biosci Biotechnol Biochem 68:271–276. doi:10.1271/bbb.68.271
Shih CM, Lin H, Liang YC, Lee WS, Bi WF, Juan SH (2004) Concentration-dependent differential effects of quercetin on rat aortic smooth muscle cells. Eur J Pharmacol 496:41–48. doi:10.1016/j.ejphar.2004.06.016
Takahashi K, Shibata T, Oba T, Ishikawa T, Yoshikawa M, Tatsunami R, Takahashi K, Tampo Y (2009) Multidrug-resistance-associated protein plays a protective role in menadione-induced oxidative stress in endothelial cells. Life Sci 84:211–217. doi:10.1016/j.lfs.2008.11.021
Vafeiadou K, Vauzour D, Rodriguez-Mateos A, Whiteman M, Williams RJ, Spencer JPE (2008) Glial metabolism of quercetin reduces its neurotoxic potential. Arch Biochem Biophys 478:195–200. doi:10.1016/j.abb.2008.07.014
Wu FYH, Liao WC, Chang HM (1993) Comparison of antitumor activity of vitamins K1, K2 and K3 on human tumor cells by two (MTT and SRB) cell viability assays. Life Sci 52:1797–1804. doi:10.1016/0024-3205(93)90469-J
Yen GC, Duh PD, Tsai HL, Huang SL (2003) Pro-oxidative properties of flavonoids in human lymphocytes. Biosci Biotechnol Biochem 67:1215–1222. doi:10.1271/bbb.67.1215
Acknowledgments
This study was supported by a grant (number: 200719023) from Eskisehir Osmangazi University Scientific Research Projects Committee. These results were presented in Meeting ‘Free Radicals and Nutrition: basic mechanisms and clinical applications’ (Berlin, 05-09.07.2008) and abstract was printed in Free Radical Research vol: 42, Supplement 1, July 2008, S82.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Oztopcu-Vatan, P., Kabadere, S. & Uyar, R. The effect of pretreatment or combined treatment of quercetin on menadione toxicity in rat primary mixed glial cells in vitro. Cytotechnology 61, 11–16 (2009). https://doi.org/10.1007/s10616-009-9235-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10616-009-9235-7