Potential benefits of quinoxaline 1, 4-dioxides in aldosterone dysmetabolism disease—A medical hypothesis
Da-Jiang Zou, Qiao-Feng Zheng, Xian-Ju Huang, Xu Wang, Awais Ihsan
DOI: 10.4236/ojas.2011.13016   PDF    HTML     4,254 Downloads   8,050 Views   Citations


Quinoxaline 1, 4-dioxides (QdNOs) are quinox-aline derivatives which have been used as an-timicrobial agents and growth promoters in animals widely. They are also assumed to cure human disease such as anticancer, antitubercular and inhibiting parasite. QdNOs such as carbadox and their major metabolites induced a special decline of aldosterone production from the swine adrenal in vivo and in vitro, and thus cause hypovolemia, hyponatremia and hyperkalemia. This can also be expected to be the case for human. As a mainly physiological hormone and a novel steroid with potent mineralocorticoid activity, aldosterone plays an important role in the pathophysiological process of brain, renal and heart disease progression and may be a renal and vascular risk factor. Here, we provide evidence to support the hypothesis that QdNOs may lead potential benefits in aldosterone dysmetabolism disease via the synthesis deficiency of aldosterone in adrenal and/or the cardiovascular tissues. If the hypothesis is true, it may provide a new option into the therapy for aldosterone dysmetabolism disease, especially in cardiovascular system, and thus assume a broader application of QdNOs.

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Zou, D. , Zheng, Q. , Huang, X. , Wang, X. and Ihsan, A. (2011) Potential benefits of quinoxaline 1, 4-dioxides in aldosterone dysmetabolism disease—A medical hypothesis. Open Journal of Animal Sciences, 1, 121-127. doi: 10.4236/ojas.2011.13016.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Suter, W., Rosselet, A. and Knusel, F. (1978) Mode of action of quindoxin and substituted quinoxaline-di-N- oxides on Escherichia coli. Antimicrob Agents Che- mother, 13, 770-783.
[2] Bertschinger, H.U. (1976) Die chemotherapeutische Wirksamkeit von Olaquindox bei Ferkeln mit experi-menteller Colidiarhoe und Colienterotoxamie. Schweiz Arch Tierheilkd, 118, 397-407.
[3] Coulthard, C.E. and Hale, L.J. (1955) The treatment of experimental bacillary infections of mice with quinoxaline 1:4 di-N-oxide. British Journal of Pharmacol, 10, 394-396.
[4] Hennessy, T.D. and Edwards, J.R. (1972) Antibacterial properties of quindoxin: A new growth promoting agent. Veterinary Record, 90, 187-191. doi:10.1136/vr.90.7.187
[5] Carta, A., Corona, P. and Loriga, M. (2005) Quinoxaline 1, 4-dioxide: A versatile scaffold endowed with manifold activities. Current Medical Chemistry, 12, 2259-2272. doi:10.2174/0929867054864831
[6] Hoskin, B.D. and Lyon, P.M. (1972) The effect of quin-doxin on the growth of broiler chickens. Veterinary Record, 90, 396-399. doi:10.1136/vr.90.14.396
[7] Kirchgessner, M. and Roth, F.X. (1977) Olaquindoxein neuer Wachstumspromotor in der Tierernahrung. III. Zur Wirksamkeit in der Kalbermast. Z. Tierphysiol. Tierer-naehr Futtermittelkd, 38, 23-28. doi:10.1111/j.1439-0396.1977.tb00204.x
[8] Qiu, Y.S., Yuan, Z.H., Fan, S.X., Liu, D.C., Huang, L.L. and Yin, J.Y. (2003) Development of liquid chromato-graphic methods for determination of cyadox and its main metabolites in edible tissues and serum of swine. Chinese Journal of Veterinary Science, 23, 363-365.
[9] Gali-Muhtasib, H.U., Diab-Assaf, M. and Haddadin, M.J. (2005) Quinoxaline 1, 4-dioxides induce G2/M cell cycle arrest and apoptosis in human colon cancer cells. Cancer Chemother Pharmacol, 55, 369-378. doi:10.1007/s00280-004-0907-x
[10] KangAe, L., obert, A.R and John, J.L. (2007) Hypoxia, drug therapy and toxicity. Pharmacology Therapeutics, 113, 229-246. doi:10.1016/j.pharmthera.2006.08.001
[11] Amin, K.M., Ismail, M.M.F., Noaman, E., Soliman, D.H. and Ammar, Y.A. (2006) New quinoxaline 1, 4-di-N-oxi- des, Part 1: Hypoxia-selective cytotoxins and anticancer agents derived from quinoxaline 1, 4-di-N-oxides. Bio-organic Medicinal Chemistry, 14, 6917-6923. doi:10.1016/j.bmc.2006.06.038
[12] Gali-Muhtasib, H.U., Haddadin, M.J., Rahhal, D.N. and Younes, I. (2001) Quinoxaline 1, 4-dioxides as anticancer and hypoxiaselective drugs. Oncology Reports, 8, 6- 79-684.
[13] Zanetti, S., Sechi, L.A., Molicotti, P., Cannas, S., Bua, A., Deriu, A., Carta, A. and Paglietti, G. (2005) In vitro ac-tivity of new quinoxalin 1, 4-dioxide derivatives against strains of Mycobacterium tuberculosis and other myco-bacteria. International Journal of Antimicrob Agents, 25, 179-181. doi:10.1016/j.ijantimicag.2004.11.003
[14] Montoya, M.E., Sainz, Y., Ortega, M.A., Lopez, D.e., Cerain, A. and Monge, A. (1998) Synthesis and an-ti-tuberculosis activity of some new 2-quinoxaline car-bonitriles. Farmaco, 53, 570-573. doi:10.1016/S0014-827X(98)00067-6
[15] Ortega, M.A., Sainz, Y., Montoya, M.E., Jaso, A., Zarranz, B., Aldana, I. and Monge, A. (2002) Anti- Mycobacterium tuberculosis agents derived from quin- oxaline-2-carbonitrile and quinoxaline-2-carbonitrile 1, 4-di-N-oxide. Arzneimittelforschung, 52, 113-119.
[16] Aguirre, G., Cerecetto, H., Maio, R.D., González, M., Alfaro, M.E.M., Jaso, A., et al. (2004) Quinoxaline N, N′-dioxide derivatives and related compounds as growth inhibitors of Trypanosoma cruzi. Structure-activity rela-tionships. Bioorganic Medicinal Chemistry Letters, 14, 3835-3839. doi:10.1016/j.bmcl.2004.04.088
[17] Jager, L.P., de Graaf, G.J., Widjaja-Greefkes, H.C.A. (1996) Screening for drug-induced alterations in the production and release of steroid hormones by porcine adrenocortical cells in vitro. Toxicol in vitro, 10, 595-608. doi:10.1016/S0887-2333(96)00047-1
[18] Jager, L.P., de Graaf, G.J., Widjaja-Greefkes, H.C.A., Accord-Burleson, C.C.F., Van, den Dungen, H.M. and Baars, A.J. (1994) Effects of feed additives and veterinary drugs on aldosterone production and release by porcine adrenal cells in vitro. Journal of Veterinary Pharmacology and Therapeutics, 17, 175-185. doi:10.1111/j.1365-2885.1994.tb00231.x
[19] van der Molen, E.J. (1988) Pathological effects of car-badox in pigs with special emphasis on the adrenal. Journal of Comparative Pathology, 98, 55-67. doi:10.1016/0021-9975(88)90030-8
[20] Spierenburg, T.J., Baars, A.J., de Graaf, G.J., Jager, L.P. (1988) Carbadox-induced inhibition of aldosterone pro-duction in porcine adrenals in vitro. Toxicol in vitro, 2, 1- 41-143. doi:10.1016/0887-2333(88)90026-4
[21] van de Kerk, P. (1985) Drug toxicity in piglets following long-term consumption of medicated feed. Tijdschr Dier- geneeskd, 110, 181-184.
[22] Rigsby, C.S., Cannady, W.E. and Dorrance, A.M. (2005) Aldosterone: Good guy or bad guy in cerebrovascular di- sease? Trends Endocrinol Metab, 16, 401-406. doi:10.1016/j.tem.2005.09.002
[23] Epstein, M. (2001) Aldosterone as a mediator of progres-sive renal disease: Pathogenetic and clinical implications. American Jorunal of Kidney Diseases, 37, 677-688. doi:10.1016/S0272-6386(01)80115-3
[24] Tan, L.B., Schlosshan, D. and Barker, D. (2004) Fiftieth anniversary of aldosterone: From discovery to cardi-ovascular therapy. International Journal of Cardiology, 96, 321-333. doi:10.1016/j.ijcard.2004.05.004
[25] Cohn, J.N. and Colucci, W. (2006) Cardiovascular Effects of Aldosterone and Post-Acute Myocardial Infarction Pathophysiology. American Jorunal of Cardiology, 97, 4-12. doi:10.1016/j.amjcard.2006.03.004
[26] Stocco, D.M. (2001) StAR protein and the regulation of steroid hormone biosynthesis. Annual Review of Physi-ology, 63, 193-213. doi:10.1146/annurev.physiol.63.1.193
[27] White, P.C. (2004) Aldosterone synthase deficiency and related disorders. Molecular and Cellular Endocrinology, 217, 81-87. doi:10.1016/j.mce.2003.10.013
[28] Lisurek, M., Bernhardt, R. (2004) Modulation of aldos-terone and cortisol synthesis on the molecular level. Mo-lecular Cellular Endocrinology, 25, 149-159. doi:10.1016/j.mce.2003.11.008
[29] Erdmann, B., Gerst, H., Lippoldt, A., Bülow, H., Ganten, D., Fuxe, K., et al. (1996) Expression of cytochrome P45011B1 in the brain of normal hypertensive transgenic rats. Brain Research, 733, 73-82. doi:10.1016/0006-8993(96)00540-9
[30] MacKenzie, S.M., Clark, C.J., Fraser, R., Gome- z-Sanchez, C.E., Connell, J.M. and Miller, W.L. (1988) Molecular biology of steroid hormone synthesis. Endo-crine Reviews, 9, 295-318. doi:10.1210/edrv-9-3-295
[31] Rudolph, A.E., Blasi, E.R. and Delyani, J.A. (2000). Tissue-specific corticosteroidogenesis in the rat. Mole-cular and Cellular Endocrinology, 165, 221-224. doi:10.1016/S0303-7207(00)00258-6
[32] Yoshimura, M., Nakamura, S., Ito, T., Nakayama, M., Harada, E., Mizuno, Y., et al. (2002) Expression of al-dosterone synthase gene in failing human heart: Quantit-ative analysis using modified real-time polymerase chain reaction. Journal of Clinical Endocrinology and Meta-bolism, 87, 3936-3940. doi:10.1210/jc.87.8.3936
[33] Xiao, F., Puddefoot, J.R. and Vinson, G.P. (2000) Aldos-terone mediates angiotensin Ⅱ-stimulated rat vascular smooth muscule cell proliferation. Journal of Endocri-nology, 165, 533-536. doi:10.1677/joe.0.1650533
[34] Slight, S.H., Joseph, J., Ganjam, V.K. and Weber, K.T. (1999) Extra-adrenal mineralocorticoids and cardiovas-cular tissue. Journal of Molecular Cellular Cardiology, 31, 1175-1184. doi:10.1006/jmcc.1999.0963
[35] Silvestre, J.S., Robert, V., Heymes, C., AupetitFaisant, B., Mouas, C., Moalic, J.M., et al. (1998) Myocardial pro-duction of aldosterone and corticosterone in the rat. Phy-siological regulation, Journal of Biology Chemistry, 273, 4883-4891. doi:10.1074/jbc.273.9.4883
[36] Ishibashi, T., Satoh, F., Yamada, T., Sato, A., Matsuhashi, T. and Takase, K. (2007) Primary aldosteronism: A pic-torial essay. Abdom Imaging, 32, 504-514. doi:10.1007/s00261-006-9151-7
[37] Young, W.F. (2003) Minireview: Primary aldosteron-ism-changing concepts in diagnosis and treatment. En-docrinology, 144, 2208-2213. doi:10.1210/en.2003-0279
[38] Calhoun, D.A. (2006) Aldosteronism and Hypertension. Clinical Journal of the American Society of Nephrology, 1, 1039-1045. doi:10.2215/CJN.01060306
[39] Cohn, J.N. and Colucci, W. (2006) Cardiovascular Effects of Aldosterone and Post-Acute Myocardial Infarction Pathophysiology. American Journal of Cardiology, 97, 4-12. doi:10.1016/j.amjcard.2006.03.004
[40] Brown, N.J. (2005) Aldosterone and end-organ damage. Current Opinion in Nephrology and Hypertension, 14, 235-241. doi:10.1097/01.mnh.0000165889.60254.98
[41] Rocha, R.C.T., Stier, Jr. (2001) Pathophysiological effects of aldosterone in cardiovascular tissues. Trends Endocrinol Metab, 12, 308-314. doi:10.1016/S1043-2760(01)00432-5
[42] Danser, A.H., van Kesteren, C.A., Bax, W.A., Tavenier, M., Derkx, F.H.M. and Saxena, P.R., et al. (1997) Pror- enin, renin, angiotensinogen, and angio-tensin-converting enzyme in normal and failing human hearts. Evidence for renin binding Circulation, 96, 220-226.
[43] Dahl?f, B. (1995) Effect of angiotensin II receptor blockade on cardiac hypertrophy and remodelling: A re-view. Journal of Human Hypertension, 9, 37-44.
[44] Tan, L.B., Schlosshan, D. and Barker, D. (2004) Fiftieth anniversary of aldosterone: From discovery to cardi-ovascular therapy. International Journal of Cardiology, 96, 321-333. doi:10.1016/j.ijcard.2004.05.004
[45] Sk?tt, O., Uhrenholt, T.R., Schjerning, J., Hansen, P.B.L., Rasmussen, L.E. and Jensen, B.L. (2006) Rapid actions of aldosterone in vascular health and disease—friend or foe? Pharmacology Therapeutics, 111, 495-507.
[46] Patel, P.D., Sherman, T.G., Goldman, D.J., Watson, S.J. (1989) Molecular cloning of a mineralocorticoid (type I) receptor complementary DNA from rat hippocampus. Molecular Endocrinology, 3, 1877-1185. doi:10.1210/mend-3-11-1877
[47] Takeda, Y., Miyamori, I., Inaba, S., Furukawa, K., Hata-keyama, H., Yoneda, T., et al. (1997) Vascular aldosterone in genetically hypertensive rats. Hypertension, 29, 45-48.
[48] Loffing, J., Summa, V., Zecevic, M. and Verrey, F. (2001) Mediators of aldosterone action in the renal tubule. Cur-rent Opinion in Nephrology and Hypertension, 10, 667-675. doi:10.1097/00041552-200109000-00019
[49] Arriza, J.L., Weinberger, C., Cerelli, G., Glaser, T.M., Handelin, B.L., Housman, D.E., et al. (1987) Cloning of human mineralocorticoid receptor complementary DNA: Structural and functional kinship with the glucocorticoid receptor. Science, 237, 268-275. doi:10.1126/science.3037703
[50] L?sel, R., Schultz, A. and Wehling, M. (2004) A quick glance at rapid aldosterone action. Molecular Cellular Endocrinology, 217, 137-141. doi:10.1016/j.mce.2003.10.018
[51] Nishizaka, M.K., Zaman, M.A. and Calhoun, D.A. (2003) Efficacy of low-dose spironolactone in subjects with re-sistant hypertension. American Journal of Hypertens, 6, 925-930. doi:10.1016/S0895-7061(03)01032-X
[52] van der Molen, E.J., De Graaf, G.J., Spierenburg, T.J., Nabuurs, M.J.A., Baars, A.J. and Jager, L.P. (1986) Hyp- oaldosteronism in piglets induced by carbadox. Expe- rientia, 42, 1247-1249. doi:10.1007/BF01946407
[53] van der Molen, E.J., Baars, A.J., De Graaf ,G.J. and Jager, L.P. (1989) Comparative study of the effect of carbadox, olaquindox and cyadox on aldosterone, sodium and po-tassium plasma levels in weaned pigs. Research in Vete-rinary Science, 47, 11-16.
[54] van der Molen, E.J., de Graaf, G.J. and Baars, A.J. (1989) Persistence of carbadox-induced adrenal lesions in pigs following drug withdrawal and recovery of aldosterone plasma concentrations. Journal of Comparative Path ology, 100, 295-300. doi:10.1016/0021-9975(89)90107-2
[55] Spierenburg, T.J., Baars, A.J., de Graaf, G.J. and Jager, L.P. (1988) Carbadox-induced inhibition of aldosterone production in porcine adrenals in vitro. Toxicol in vitro, 2, 141-143. doi:10.1016/0887-2333(88)90026-4
[56] Huang, X.J., Ihsan, A., Wang, X., Dai, M.H., Wang, Y.L., Su, S.J., Xue, X.J. and Yuan, Z.H. (2009) Long-term dose-dependent response of Mequindox on aldosterone, corticosterone and five steroidogenic enzyme mRNA in the adrenal of male rats. Toxicology Letters, 191, 167-173. doi:10.1016/j.toxlet.2009.08.021
[57] Huang, X.J., Zhang, H.H., Wang, X., Huang ,L.L., Zhang, L.Y., Yan, C.X. and Yuan, Z.H. (2010) ROS mediated cytotoxicity of porcine adrenocortical cells induced by QdNOs derivatives in vitro. Chemico-Biologicol Interac-tions, 185, 227-234. doi:10.1016/j.cbi.2010.02.030
[58] Huang, X.J., Wang, X., Ihsan, A., Liu, Q., Xue, X.J., Su, S.J., Yang, C.H. and Yuan, Z.H. (2010) Interactions of NADPH oxidase, renin-angiotensin-aldosterone system and reactive oxigen species in mequindox-mediated al-dosterone secretion in wistar. Toxicology Letters, 198, 112-118. doi:10.1016/j.toxlet.2010.05.013
[59] Ajani, A.E., Marwick, T.H. and Krum, H. (2006) Aldos-terone antagonists: A new treatment option for patients with post-myocardial infarction heart failure. Cardi-ovascular Revascularization Medicine, 7, 234-236. doi:10.1016/j.carrev.2006.07.002
[60] FAO/WHO (1990) Joint Expert Committee on Food Ad-ditives: Evaluation of certain veterinary drug residues in food. Technology Services, 799, 45.

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