The critical role of oxidative stress in the toxicity and metabolism of quinoxaline 1,4-di-N-oxides in vitro and in vivo

Drug Metabolism Reviews

Volumn 48, Issue 2, 2016, Pages 159-182

  Wang, Xu ^a,b   Martínez, María Aránzazu ^b   Cheng, Guyue ^a   Liu, Zhaoying ^c   Huang, Lingli ^a   Dai, Menghong ^a   Chen, Dongmei ^a   Martínez Larrañaga, María Rosa ^b   Anadón, Arturo ^b   Yuan, Zonghui ^a,d  

^a HUAZHONG AGRICULTURAL UNIVERSITY   (China)

^b UNIVERSIDAD COMPLUTENSE DE MADRID   (Spain)

^c HUNAN AGRICULTURAL UNIVERSITY   (China)

^d Hubei Collaborative Innovation Centre for Animal Nutrition and Feed Safety   (China)

Author keywords

antioxidants; carbadox; cyadox; mequindox; olaquindox; oxidative stress; quinocetone; Quinoxaline; reactive oxygen species

Indexed keywords

ALDEHYDE OXIDASE; CARBADOX; CARBONYL REDUCTASE; CIADOX; CYTOCHROME P450; JANUS KINASE; KELCH LIKE ECH ASSOCIATED PROTEIN 1; MEQUINDOX; MITOGEN ACTIVATED PROTEIN KINASE; MYC PROTEIN; OLAQUINDOX; QUINOCETONE; QUINOXALINE; QUINOXALINE 1,4 DI N OXIDE; REACTIVE OXYGEN METABOLITE; STAT PROTEIN; TRANSCRIPTION FACTOR NRF2; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG; XANTHINE OXIDASE; QUINOXALINE DERIVATIVE;

ANTIOXIDANT ACTIVITY; APOPTOSIS; AUTOPHAGY; CELL CYCLE; DNA DAMAGE; ENDOPLASMIC RETICULUM STRESS; HUMAN; HYDROXYLATION; IN VITRO STUDY; IN VIVO STUDY; INTRACELLULAR SIGNALING; METABOLISM; NONHUMAN; OXIDATIVE STRESS; REDUCTION; REVIEW; TOXICITY TESTING; ANIMAL;

ANIMALS; HUMANS; OXIDATIVE STRESS; QUINOXALINES;

EID: 84977581842     PISSN: 03602532     EISSN: 10979883     Source Type: Journal    
DOI: 10.1080/03602532.2016.1189560     Document Type: Review

References (156)

1. L.Adams, M.C.Franco, A.G.Estevez (2015). Reactive nitrogen species in cellular signaling. Exp Biol Med (Maywood) 240:711–717.
2. R.F.Anderson, S.S.Shinde, M.P.Hay, W.A.Denny (2006). Potentiation of the cytotoxicity of the anticancer agent tirapazamine by benzotriazine N-oxides: The role of redox equilibria. J Am Chem Soc 128:245–249.
3. O.O.Ajani (2014). Present status of quinoxaline motifs: Excellent pathfinders in therapeutic medicine. Eur J Med Chem 85:688–715.
4. A.Azqueta, L.Arbillaga, G.Pachon,. (2007). A quinoxaline 1,4-di-N-oxide derivative induces DNA oxidative damage not attenuated by vitamin C and E treatment. Chem Biol Interact 168:95–105.
5. S.N.Baviskar, M.S.Shields (2010). RNAi silenced Dd-grp94 (Dictyostelium discoideum glucose-regulated protein 94 kDa) cell lines in Dictyostelium exhibit marked reduction in growth rate and delay in development. Gene Expr 15:75–87.
6. H.Belhadjali, M.C.Marguery, F.Journe,. (2002). Allergic and photoallergic contact dermatitis to Olaquindox in a pig breeder with prolonged photosensitivity. Photodermatol Photoimmunol Photomed 18:52–53.
7. L.Beutin, E.Preller, B.Kowalski (1981). Mutagenicity of quindoxin, its metabolites, and two substituted quinoxaline-di-N-oxides. Antimicrob Agents Chemother 20:336–343.
8. A.Carta, P.Corona, M.Loriga (2005). Quinoxaline 1,4-dioxide: A versatile scaffold endowed with manifold activities. Curr Med Chem 12:2259–2272.
9. A.Carta, S.Piras, G.Loriga, G.Paglietti (2006). Chemistry, biological properties and SAR analysis of quinoxalinones. Mini Rev Med Chem 6:1179–1200.
10. M.Cerna, K.Angelis (1986). Mutagenic action of the quinoxaline-type growth promotors on microorganisms. Biologizace a Chemizace Zivocisne Vyroby – Veterinaria 22:9–15.
11. C.Chen, G.Cheng, H.Hao,. (2013). Mechanism of porcine liver xanthine oxidoreductase mediated N-oxide reduction of cyadox as revealed by docking and mutagenesis studies. PLoS One 8:e73912.
12. Q.Chen, S.Tang, X.Jin,. (2009). Investigation of the genotoxicity of quinocetone, carbadox and olaquindox in vitro using Vero cells. Food Chem Toxicol 47:328–334.
13. L.L.Cheng, Z.H.Wang, J.Z.Shen,. (2012). A specific UPLC-ESI-MS/MS method for analysis of cyadox and its three main metabolites in fish samples. Anal Methods 4:217–221.
14. X.X.Cheng, Z.H.Yuan, S.X.Fan, J.F.Yuan (2004). Effect of cyadox on growth performance of carp and Prussian carp. Chin Reserv Fish 24:52–54.
15. China. (2001). Ministry of Agriculture Bulletin, No. 168, feed additive drug use norms.
16. China. (2003). Ministry of Agriculture, PR China, Notice No. 295. .
17. G.Chowdhury, D.Kotandeniya, J.S.Daniels,. (2004). Enzyme-activated, hypoxia-selective DNA damage by 3-amino-2-quinoxalinecarbonitrile 1,4-di-N-oxide. Chem Res Toxicol 17:1399–1405.
18. B.A.Croker, D.L.Krebs, J.G.Zhang,. (2003). SOCS3 negatively regulates IL-6 signaling in vivo. Nat Immunol 4:540–545.
19. C.Dai, S.Tang, D.Li,. (2015). Curcumin attenuates quinocetone-induced oxidative stress and genotoxicity in human hepatocyte L02 cells. Toxicol Mech Methods 25:340–346.
20. A.Das, D.Choudhury, S.Chakrabarty,. (2012). Acenaphthenequinone induces cell cycle arrest and mitochondrial apoptosis via disruption of cellular microtubules. Toxicol Res 1:171–185.
21. M.Dewaele, H.Maes, P.Agostinis (2010). ROS-mediated mechanisms of autophagy stimulation and their relevance in cancer therapy. Autophagy 6:838–854.
22. H.Ding, Y.Liu, Z.Zeng,. (2012). Pharmacokinetics of mequindox and one of its major metabolites in chickens after intravenous, intramuscular and oral administration. Res Vet Sci 93:374–377.
23. M.X.Ding, Y.L.Wang, H.L.Zhu, Z.H.Yuan (2006). Effects of cyadox and olaquindox on intestinal mucosal immunity and on fecal shedding of Escherichia coli in piglets. J Anim Sci 84:2367–2373.
24. M.X.Ding, Z.H.Yuan, Y.L.Wang,. (2006b). Olaquindox and cyadox stimulate growth and decrease intestinal mucosal immunity of piglets orally inoculated with Escherichia coli. J Anim Physiol Anim Nutr (Berl) 90:238–243.
25. EC. (1976). Commission Regulation (EC) No. 1608/76 Off J Eur Commun L364: 3norms.
26. EC. (1998). Commission Regulation (EC) No. 2788/98. Off J Eur Commun L347/31.
27. S.X.Fan, Z.H.Yuan, D.J.Wang,. (2000). Antibacterial activity in vitro of cyadox. J Huazhong Agri Univ 419:51–54.
28. G.Fang, Q.He, S.Zhou,. (2006). Subchronic oral toxicity study with cyadox in Wistar rats. Food Chem Toxicol 44:36–41.
29. FAO/WHO. (1990). Joint Expert Committee on Food Additives. Evaluation of certain veterinary drug residues in good, Technical Series No. 799:45–54.
30. J.Fekadu, A.Rami (2015). Beclin-1 deficiency alters autophagosome formation, lysosome biogenesis and enhances neuronal vulnerability of HT22 hippocampal cells. Mol Neurobiol. 1-10. DOI: 10.1007/s12035-015-9453-2.
31. X.Gong, V.N.Ivanov, T.K.Hei (2015). 2,3,5,6-Tetramethylpyrazine (TMP) down-regulated arsenic-induced heme oxygenase-1 and ARS2 expression by inhibiting Nrf2, NF-kappaB, AP-1 and MAPK pathways in human proximal tubular cells. Arch Toxicol. 1-14. DOI: 10.1007/s00204-015-1600-z.
32. D.Guvenc, A.Aksoy, A.Gacar,. (2014). Evaluation of changes in monoamine levels and apoptosis induced by cyfluthrin in rats. Toxicol Res 3:331–340.
33. C.C.He, D.J.Klionsky (2009). Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 43:67–93.
34. Q.He, G.Fang, Y.Wang,. (2006). Experimental evaluation of cyadox phototoxicity to Balb/c mouse skin. Photodermatol Photoimmunol Photomed 22:100–104.
35. H.K.Henderickx, I.J.Vervaeke, J.A.Decuypere, N.A.Dierick (1982). Effect of growth promoting agents on the intestinal gut flora. Fortschr Vet 33:56–63.
36. Y.Higuchi (2003). Chromosomal DNA fragmentation in apoptosis and necrosis induced by oxidative stress. Biochem Pharmacol 66:1527–1535.
37. L.Huang, Z.Lin, X.Zhou,. (2015a). Estimation of residue depletion of cyadox and its marker residue in edible tissues of pigs using physiologically based pharmacokinetic modelling. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 32:2002–2017.
38. L.Huang, F.Yin, Y.Pan,. (2015b). Metabolism, distribution, and elimination of mequindox in pigs, chickens, and rats. J Agric Food Chem 63:9839–9849.
39. L.L.Huang, N.Xu, S.Harnud,. (2015c). Metabolic disposition and elimination of cyadox in pigs, chickens, carp, and rats. J Agric Food Chem 63:5557–5569.
40. Q.Huang, A.Ihsan, P.Guo,. (2016). Evaluation of the safety of primary metabolites of cyadox: Acute and sub-chronic toxicology studies and genotoxicity assessment. Regul Toxicol Pharmacol 74:123–136.
41. X.J.Huang, A.Ihsan, X.Wang,. (2009). Long-term dose-dependent response of Mequindox on aldosterone, corticosterone and five steroidogenic enzyme mRNAs in the adrenal of male rats. Toxicol Lett 191:167–173.
42. X.J.Huang, X.Wang, A.Ihsan,. (2010a). Interactions of NADPH oxidase, renin-angiotensin-aldosterone system and reactive oxygen species in mequindox-mediated aldosterone secretion in Wistar rats. Toxicol Lett 198:112–118.
43. X.J.Huang, H.H.Zhang, X.Wang,. (2010b). ROS mediated cytotoxicity of porcine adrenocortical cells induced by QdNOs derivatives in vitro. Chem Biol Interact 185:227–234.
44. A.Ihsan, X.Wang, X.J.Huang,. (2010). Acute and subchronic toxicological evaluation of mequindox in Wistar rats. Regul Toxicol Pharmacol 57:307–314.
45. A.Ihsan, X.Wang, Z.Liu,. (2011). Long-term mequindox treatment induced endocrine and reproductive toxicity via oxidative stress in male Wistar rats. Toxicol Appl Pharmacol 252:281–288.
46. A.Ihsan, X.Wang, H.G.Tu,. (2013a). Genotoxicity evaluation of mequindox in different short-term tests. Food Chem Toxicol 51:330–336.
47. A.Ihsan, X.Wang, W.Zhang,. (2013b). Genotoxicity of quinocetone, cyadox and olaquindox in vitro and in vivo. Food Chem Toxicol 59:207–214.
48. P.Juin, A.O.Hueber, T.Littlewood, G.Evan (1999). c-Myc-induced sensitization to apoptosis is mediated through cytochrome c release. Genes Dev 13:1367–1381.
49. C.Kantari, H.Walczak (2011). Caspase-8 and bid: Caught in the act between death receptors and mitochondria. Biochim Biophys Acta 1813:558–563.
50. Y.W.Ki, J.E.Lee, J.H.Park,. (2012). Reactive oxygen species and mitogen-activated protein kinase induce apoptotic death of SH-SY5Y cells in response to fipronil. Toxicol Lett 211:18–28.
51. H.G.Kim, Y.R.Kim, J.H.Park,. (2015). Endosulfan induces COX-2 expression via NADPH oxidase and the ROS, MAPK, and Akt pathways. Arch Toxicol 89:2039–2050.
52. M.S.Klaric, S.Pepeljnjak, A.M.Domijan, J.Petrik (2007). Lipid peroxidation and glutathione levels in porcine kidney PK15 cells after individual and combined treatment with fumonisin B(1), beauvericin and ochratoxin A. Basic Clin Pharmacol Toxicol 100:157–164.
53. J.Klefstrom, E.W.Verschuren, G.Evan (2002). c-Myc augments the apoptotic activity of cytosolic death receptor signaling proteins by engaging the mitochondrial apoptotic pathway. J Biol Chem 277:43224–43232.
54. M.Kobayashi, M.Yamamoto (2005). Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation. Antioxid Redox Signal 7:385–394.
55. F.N.Lai, J.Y.Ma, J.C.Liu,. (2015). The influence of N-acetyl-l-cysteine on damage of porcine oocyte exposed to zearalenone in vitro. Toxicol Appl Pharmacol 289:341–348.
56. S.A.Lakhani, A.Masud, K.Kuida,. (2006). Caspases 3 and 7: Key mediators of mitochondrial events of apoptosis. Science 311:847–851.
57. R.Lang, A.L.Pauleau, E.Parganas,. (2003). SOCS3 regulates the plasticity of gp130 signaling. Nat Immunol 4:546–550.
58. J.E.Lee, J.S.Kang, Y.W.Ki,. (2011a). Akt/GSK3β signaling is involved in fipronil-induced apoptotic cell death of human neuroblastoma SH-SY5Y cells. Toxicol Lett 202:133–141.
59. S.J.Lee, H.P.Kim, Y.Jin,. (2011b). Beclin 1 deficiency is associated with increased hypoxia-induced angiogenesis. Autophagy 7:829–839.
60. L.K.Leung, Y.Su, R.Chen,. (2001). Theaflavins in black tea and catechins in green tea are equally effective antioxidants. J Nutr 131:2248–2251.
61. G.Y.Li, M.Kim, J.H.Kim,. (2008). Gene expression profiling in human lung fibroblast following cadmium exposure. Food Chem Toxicol 46:1131–1137.
62. J.Li, L.Huang, X.Wang,. (2014a). Metabolic disposition and excretion of quinocetone in rats, pigs, broilers, and carp. Food Chem Toxicol 69:109–119.
63. J.Li, L.L.Huang, Y.H.Pan,. (2014b). Tissue depletion of quinocetone and its five major metabolites in pigs, broilers, and carp fed quinocetone premix. J Agric Food Chem 62:10348–10356.
64. J.H.Li, X.R.Liu, Y.Zhang,. (2012). Toxicity of nano zinc oxide to mitochondria. Toxicol Res 1:137–144.
65. W.Li, A.N.Kong (2009). Molecular mechanisms of Nrf2-mediated antioxidant response. Mol Carcinog 48:91–104.
66. Y.J.Li, T.Shimizu, Y.Hirata,. (2013). EM, EM703 inhibit NF-kB activation induced by oxidative stress from diesel exhaust particle in human bronchial epithelial cells: Importance in IL-8 transcription. Pulm Pharmacol Ther 26:318–324.
67. Z.Li, C.Yu, X.Chen,. (2015). [Research on olaquindox induced endoplasmic reticulum stress related apoptosis on nephrotoxicity]. Wei Sheng Yan Jiu 44:444–450.
68. Y.C.Liao, Y.F.Chen, T.C.Lee (2015). Increased susceptibility of H-Ras(G12V)-transformed human urothelial cells to the genotoxic effects of sodium arsenite. Arch Toxicol 89:1971–1979.
69. H.Lingli, X.Ning, S.Harnud,. (2015). Metabolic disposition and elimination of cyadox in pigs, chickens, carp, and rats. J Agric Food Chem 63:5557–5569.
70. P.Lirk, G.Hoffmann, J.Rieder (2002). Inducible nitric oxide synthase-time for reappraisal. Curr Drug Targets Inflamm Allergy 1:89–108.
71. J.Liu, X.H.Ge, O.Y.Man,. (2011a). Catalytic characteristics of CYP3A22-dependent mequindox detoxification. Catal Commun 12:637–643.
72. J.Liu, M.Ouyang, J.Jiang,. (2012). Mequindox induced cellular DNA damage via generation of reactive oxygen species. Mutat Res 741:70–75.
73. Z.Liu, L.Huang, M.Dai,. (2009). Metabolism of cyadox in rat, chicken and pig liver microsomes and identification of metabolites by accurate mass measurements using electrospray ionization hybrid ion trap/time-of-flight mass spectrometry. Rapid Commun Mass Spectrom 23:2026–2034.
74. Z.Liu, L.Huang, M.Dai,. (2008). Metabolism of olaquindox in rat liver microsomes: Structural elucidation of metabolites by high-performance liquid chromatography combined with ion trap/time-of-flight mass spectrometry. Rapid Commun Mass Spectrom 22:1009–1016.
75. Z.Y.Liu, L.L.Huang, D.M.Chen,. (2010a). Application of electrospray ionization hybrid ion trap/time-of-flight mass spectrometry in the rapid characterization of quinocetone metabolites formed in vitro. Anal Bioanal Chem 396:1259–1271.
76. Z.Y.Liu, L.L.Huang, D.M.Chen,. (2010b). The metabolism and N-oxide reduction of olaquindox in liver preparations of rats, pigs and chicken. Toxicol Lett 195:51–59.
77. Z.Y.Liu, L.L.Huang, D.M.Chen, Z.H.Yuan (2010c). Metabolism of mequindox in liver microsomes of rats, chicken and pigs. Rapid Commun Mass Spectrom 24:909–918.
78. Z.Y.Liu, L.L.Huang, X.N.Zhou,. (2011b). The metabolism of olaquindox in rats, chickens and pigs. Toxicol Lett 200:24–33.
79. Z.Y.Liu, Z.L.Sun (2013). The metabolism of carbadox, olaquindox, mequindox, quinocetone and cyadox: An overview. Med Chem 9:1017–1027.
80. Z.Y.Liu, Y.F.Tao, D.M.Chen,. (2011c). Identification of carbadox metabolites formed by liver microsomes from rats, pigs and chickens using high-performance liquid chromatography combined with hybrid ion trap/time-of-flight mass spectrometry. Rapid Commun Mass Spectrom 25:341–348.
81. Y.C.Ma, N.Su, X.J.Shi,. (2015). Jaridonin-induced G2/M phase arrest in human esophageal cancer cells is caused by reactive oxygen species-dependent Cdc2-tyr15 phosphorylation via ATM-Chk1/2-Cdc25C pathway. Toxicol Appl Pharmacol 282:227–236.
82. S.Mishra, P.D.Dwivedi, H.P.Pandey, M.Das (2014). Role of oxidative stress in Deoxynivalenol induced toxicity. Food Chem Toxicol 72:20–29.
83. P.Mu, M.Zheng, M.Xu,. (2014). N-oxide reduction of quinoxaline-1,4-dioxides catalyzed by porcine aldehyde oxidase SsAOX1. Drug Metab Dispos 42:511–519.
84. M.Munz, C.Kieu, B.Mack,. (2004). The carcinoma-associated antigen EpCAM upregulates c-myc and induces cell proliferation. Oncogene 23:5748–5758.
85. K.Nakayama, N.Nakayama, T.L.Wang, M.Shih Ie (2007). NAC-1 controls cell growth and survival by repressing transcription of Gadd45GIP1, a candidate tumor suppressor. Cancer Res 67:8058–8064.
86. D.W.Nicholson, A.Ali, N.A.Thornberry,. (1995). Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 376:37–43.
87. A.B.Niculescu, 3rd, X.Chen, M.Smeets,. (1998). Effects of p21(Cip1/Waf1) at both the G1/S and the G2/M cell cycle transitions: pRb is a critical determinant in blocking DNA replication and in preventing endoreduplication. Mol Cell Biol 18:629–643.
88. T.Nunoshiba, H.Nishioka (1989). Genotoxicity of quinoxaline 1,4-dioxide derivatives in Escherichia coli and Salmonella typhimurium. Mutat Res 217:203–209.
89. J.Oh, M.W.Hur, C.E.Lee (2009). SOCS1 protects protein tyrosine phosphatases by thioredoxin upregulation and attenuates Jaks to suppress ROS-mediated apoptosis. Oncogene 28:3145–3156.
90. G.Paradies, G.Petrosillo, M.Pistolese, F.M.Ruggiero (2000). The effect of reactive oxygen species generated from the mitochondrial electron transport chain on the cytochrome c oxidase activity and on the cardiolipin content in bovine heart submitochondrial particles. FEBS Lett 466:323–326.
91. J.H.Park, Y.S.Park, J.B.Lee,. (2015). Meloxicam inhibits fipronil-induced apoptosis via modulation of the oxidative stress and inflammatory response in SH-SY5Y cells. J Appl Toxicol 36:10–23.
92. L.M.Pedruzzi, M.B.Stockler-Pinto, M.Leite, Jr., D.Mafra (2012). Nrf2-keap1 system versus NF-κB: The good and the evil in chronic kidney disease? Biochimie 94:2461–2466.
93. G.Petrosillo, F.M.Ruggiero, M.Pistolese, G.Paradies (2001). Reactive oxygen species generated from the mitochondrial electron transport chain induce cytochrome c dissociation from beef-heart submitochondrial particles via cardiolipin peroxidation. Possible role in the apoptosis. FEBS Lett 509:435–438.
94. A.G.Pirinccioglu, D.Gokalp, M.Pirinccioglu,. (2010). Malondialdehyde (MDA) and protein carbonyl (PCO) levels as biomarkers of oxidative stress in subjects with familial hypercholesterolemia. Clin Biochem 43:1220–1224.
95. M.Pospisil, I.Pipalova, L.Novacek (1986). Therapeutic efficiency of olaquindox in gamma-irradiated mice. Strahlenther Onkol 162:793–797.
96. V.Romanov, T.C.Whyard, W.C.Waltzer,. (2015). Aristolochic acid-induced apoptosis and G2 cell cycle arrest depends on ROS generation and MAP kinases activation. Arch Toxicol 89:47–56.
97. M.Scheutwinkel-Reich, W.Vd Hude (1984). Sister-chromatid exchange in Chinese hamster V79 cells exposed to quindoxin, carbadox and olaquindox. Mutat Res 139:199–202.
98. B.Sevcik (1986). Research of harmless and safety of application of the growth promoter cyadox. Workshop 1:93.
99. Z.Shaukat, D.Liu, R.Hussain,. (2015). The role of JNK signalling in responses to oxidative DNA damage. Curr Drug Targets 17:154–163.
100. J.Shi, B.Sun, W.Shi,. (2015). Decreasing GSH and increasing ROS in chemosensitivity gliomas with IDH1 mutation. Tumour Biol 36:655–662.
101. C.Stirone, S.P.Duckles, D.N.Krause, V.Procaccio (2005). Estrogen increases mitochondrial efficiency and reduces oxidative stress in cerebral blood vessels. Mol Pharmacol 68:959–965.
102. H.Stockmann-Juvala, J.Mikkola, J.Naarala,. (2004b). Fumonisin B1-induced toxicity and oxidative damage in U-118MG glioblastoma cells. Toxicology 202:173–183.
103. N.C.Sumedha, S.Miltonprabu (2015). Cardiac mitochondrial oxidative stress and dysfunction induced by arsenic and its amelioration by diallyl trisulphide. Toxicol Res 4:291–301.
104. H.Tabassum, S.Parvez, S.T.Pasha,. (2010). Protective effect of lipoic acid against methotrexate-induced oxidative stress in liver mitochondria. Food Chem Toxicol 48:1973–1979.
105. H.Tanaka, I.Matsumura, S.Ezoe,. (2002). E2F1 and c-Myc potentiate apoptosis through inhibition of NF-kappaB activity that facilitates MnSOD-mediated ROS elimination. Mol Cell 9:1017–1029.
106. X.Tang, P.Mu, J.Wu,. (2012). Carbonyl reduction of mequindox by chicken and porcine cytosol and cloned carbonyl reductase 1. Drug Metab Dispos 40:788–795.
107. M.Trinei, M.Giorgio, A.Cicalese,. (2002). A p53-p66Shc signalling pathway controls intracellular redox status, levels of oxidation-damaged DNA and oxidative stress-induced apoptosis. Oncogene 21:3872–3878.
108. O.Vafa, M.Wade, S.Kern,. (2002). c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: A mechanism for oncogene-induced genetic instability. Mol Cell 9:1031–1044.
109. E.Vicente, S.Perez-Silanes, L.M.Lima,. (2009). Selective activity against Mycobacterium tuberculosis of new quinoxaline 1,4-di-N-oxides. Bioorg Med Chem 17:385–389.
110. J.Vina, J.Sastre, F.V.Pallardo,. (2006). Role of mitochondrial oxidative stress to explain the different longevity between genders: Protective effect of estrogens. Free Radic Res 40:1359–1365.
111. S.Vircheva, G.Nenkova, A.Georgieva,. (2012). Effects of desipramine on the antioxidant status in rat tissues at carrageenan-induced paw inflammation. Cell Biochem Funct 30:18–23.
112. C.E.Voogd, J.J.van der Stel, J.J.Jacobs (1980). The mutagenic action of quindoxin, carbadox, olaquindox and some other N-oxides on bacteria and yeast. Mutat Res 78:233–242.
113. D.Wang, Y.Zhong, X.Luo,. (2011a). Pu-erh black tea supplementation decreases quinocetone-induced ROS generation and oxidative DNA damage in Balb/c mice. Food Chem Toxicol 49:477–484.
114. H.Wang, L.Wei, C.Li,. (2015a). CDK5RAP1 deficiency induces cell cycle arrest and apoptosis in human breast cancer cell line by the ROS/JNK signaling pathway. Oncol Rep 33:1089–1096.
115. X.Wang, G.J.Fang, Y.L.Wang,. (2011a). Two generation reproduction and teratogenicity studies of feeding cyadox in Wistar rats. Food Chem Toxicol 49:1068–1079.
116. X.Wang, Q.H.He, Y.L.Wang,. (2011b). A chronic toxicity study of cyadox in Wistar rats. Regul Toxicol Pharmacol 59:324–333.
117. X.Wang, X.J.Huang, A.Ihsan,. (2011c). Metabolites and JAK/STAT pathway were involved in the liver and spleen damage in male Wistar rats fed with mequindox. Toxicology 280:126–134.
118. X.Wang, D.Wan, A.Ihsan,. (2015b). Mechanism of adrenocortical toxicity induced by quinocetone and its bidesoxy-quinocetone metabolite in porcine adrenocortical cells in vitro. Food Chem Toxicol 84:115–124.
119. X.Wang, Q.Wu, D.Wan,. (2016a). Fumonisins: Oxidative stress-mediated toxicity and metabolism in vivo and in vitro. Arch Toxicol 90:81–101.
120. X.Wang, P.Yang, J.Li,. (2016b). Genotoxic risk of quinocetone and its possible mechanism in in vitro studies. Toxicol Res. 5:446–460.
121. X.Wang, H.Zhang, L.Huang,. (2015c). Deoxidation rates play a critical role in DNA damage mediated by important synthetic drugs, quinoxaline 1,4-dioxides. Chem Res Toxicol 28:470–481.
122. X.Wang, W.Zhang, Y.Wang,. (2010). Acute and sub-chronic oral toxicological evaluations of quinocetone in Wistar rats. Regul Toxicol Pharmacol 58:421–427.
123. X.Wang, W.Zhou, A.Ihsan,. (2015d). Assessment of thirteen-week subchronic oral toxicity of cyadox in Beagle dogs. Regul Toxicol Pharmacol 73:652–659.
124. Y.Wang, Z.Yuan, H.Zhu,. (2005). Effect of cyadox on growth and nutrient digestibility in weanling pigs. S Afr J Anim Sci 35:117–125.
125. Z.Wang, C.Zhang, Z.Hong,. (2013). C/EBP homologous protein (CHOP) mediates neuronal apoptosis in rats with spinal cord injury. Exp Ther Med 5:107–111.
126. T.Watanabe, S.Sekine, I.Naguro,. (2015). Apoptosis signal-regulating kinase 1 (ASK1)-p38 pathway-dependent cytoplasmic translocation of the orphan nuclear receptor NR4A2 is required for oxidative stress-induced necrosis. J Biol Chem 290:10791–10803.
127. WHO (1991a). World Health Organization. Toxicological evaluation of certain veterinary drug residues in food. Carbadox. WHO Food Additives Series, No. 27, No. 700:1–18 on INCHEM.
128. WHO (1991b). World Health Organization. Toxicological evaluation of certain veterinary drug residues in food. Olaquindox. WHO Food Additives Series, No. 27, No. 701:1–18 on INCHEM.
129. K.N.Woodward (2008). Assessment of user safety, exposure and risk to veterinary medicinal products in the European union. Regul Toxicol Pharmacol 50:114–128.
130. H.Wu, L.Li, J.Shen,. (2012). In vitro metabolism of cyadox in rat, chicken and swine using ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry. J Pharm Biomed Anal 67-68:175–185.
131. N.Xu, L.Huang, Z.Liu,. (2011). Metabolism of cyadox by the intestinal mucosa microsomes and gut flora of swine, and identification of metabolites by high-performance liquid chromatography combined with ion trap/time-of-flight mass spectrometry. Rapid Commun Mass Spectrom 25:2333–2344.
132. V.Yadav, S.Sultana, J.Yadav, N.Saini (2012). Gatifloxacin induces S and G2-phase cell cycle arrest in pancreatic cancer cells via p21/p27/p53. PLoS One 7:e47796
133. H.Y.Yang, T.H.Lee (2015). Antioxidant enzymes as redox-based biomarkers: A brief review. BMB Rep 48:200–208.
134. J.Yang, Z.Liu, M.Li, X.Qiu (2013a). Hydroxylation of quinocetone and carbadox is mediated by CYP1As in the chicken (Gallus gallus). Comp Biochem Physiol C Toxicol Pharmacol 158:84–90.
135. K.M.Yang, B.M.Kim, J.B.Park (2014). omega-Hydroxyundec-9-enoic acid induces apoptosis through ROS-mediated endoplasmic reticulum stress in non-small cell lung cancer cells. Biochem Biophys Res Commun 448:267–273.
136. W.Yang, J.Fu, X.Xiao,. (2013b). Quinocetone triggers oxidative stress and induces cytotoxicity and genotoxicity in human peripheral lymphocytes of both genders. J Sci Food Agric 93:1317–1325.
137. Y.Yang, L.Jiang, Y.She,. (2015). Olaquindox induces DNA damage via the lysosomal and mitochondrial pathway involving ROS production and p53 activation in HEK293 cells. Environ Toxicol Pharmacol 40:792–799.
138. H.Yoshimura (2002). Teratogenic assessment of carbadox in rats. Toxicol Lett 129:115–118.
139. H.Yoshimura, M.Nakamura, T.Koeda, K.Yoshikawa (1981). Mutagenicities of carbadox and olaquindox-growth promoters for pigs. Mutat Res 90:49–55.
140. M.Yu, D.Wang, M.J.Xu,. (2014). Quinocetone-induced Nrf2/HO-1 pathway suppression aggravates hepatocyte damage of Sprague-Dawley rats. Food Chem Toxicol 69:210–219.
141. M.Yu, M.J.Xu, Y.Liu,. (2013). Nrf2/ARE is the potential pathway to protect Sprague-Dawley rats against oxidative stress induced by quinocetone. Regul Toxicol Pharmacol 66:279–285.
142. C.M.Zhang, C.C.Wang, S.S.Tang,. (2013). TNFR1/TNF-alpha and mitochondria interrelated signaling pathway mediates quinocetone-induced apoptosis in HepG2 cells. Food Chem Toxicol 62:825–838.
143. K.Zhang, X.Wang, C.Wang,. (2015). Investigation of quinocetone-induced mitochondrial damage and apoptosis in HepG2 cells and compared with its metabolites. Environ Toxicol Pharmacol 39:555–567.
144. K.Zhang, W.Zheng, H.Zheng,. (2014). Identification of oxidative stress and responsive genes of HepG2 cells exposed to quinocetone, and compared with its metabolites. Cell Biol Toxicol 30:313–329.
145. T.Zhang, S.S.Tang, X.Jin,. (2011). c-Myc influences olaquindox-induced apoptosis in human hepatoma G2 cells. Mol Cell Biochem 354:253–261.
146. D.Zhao, C.Wang, S.Tang,. (2015). Reactive oxygen species-dependent JNK downregulated olaquindox-induced autophagy in HepG2 cells. J Appl Toxicol 35:709–716.
147. W.X.Zhao, S.S.Tang, X.Jin,. (2013). Olaquindox-induced apoptosis is suppressed through p38 MAPK and ROS-mediated JNK pathways in HepG2 cells. Cell Biol Toxicol 29:229–238.
148. X.J.Zhao, C.Huang, H.Lei,. (2011). Dynamic metabolic response of mice to acute mequindox exposure. J Proteome Res 10:5183–5190.
149. M.Zheng, J.Jiang, J.Wang,. (2011). The mechanism of enzymatic and non-enzymatic N-oxide reductive metabolism of cyadox in pig liver. Xenobiotica 41:964–971.
150. F.Zhou, W.Sun, M.Zhao (2015a). Controlled formation of emulsion gels stabilized by salted myofibrillar protein under malondialdehyde (MDA)-induced oxidative stress. J Agric Food Chem 63:3766–3777.
151. J.Zhou, C.Li, L.Wang,. (2015b). Hepatoprotective effects of a Chinese herbal formulation, Yingchen decoction, on olaquindox-induced hepatopancreas injury in Jian carp (Cyprinus carpio var. Jian). Fish Physiol Biochem 41:153–163.
152. S.Zhu, Y.Wang, J.Jin,. (2012). Endoplasmic reticulum stress mediates aristolochic acid I-induced apoptosis in human renal proximal tubular epithelial cells. Toxicol In Vitro 26:663–671.
153. D.B.Zorov, M.Juhaszova, S.J.Sollott (2014). Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev 94:909–950.
154. J.Zou, Q.Chen, X.Jin,. (2011). Olaquindox induces apoptosis through the mitochondrial pathway in HepG2 cells. Toxicology 285:104–113.
155. J.Zou, Q.Chen, S.Tang,. (2009). Olaquindox-induced genotoxicity and oxidative DNA damage in human hepatoma G2 (HepG2) cells. Mutat Res 676:27–33.
156. L.Zuo, T.Zhou, B.K.Pannell,. (2015). Biological and physiological role of reactive oxygen species-the good, the bad and the ugly. Acta Physiol (Oxf) 214:329–348.