title: Metabolites and JAK/STAT pathway were involved in the liver and spleen damage in male Wistar rats fed with mequindox.
abstract: Mequindox (MEQ) is a novel synthetic quinoxaline 1,4-dioxides antibacterial agent and growth promoter in animal husbandry. This study was to investigate whether reactive oxygen species (ROS), the Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway, suppressors of cytokine signaling (SOCS) and inflammatory cytokines were involved in toxicities of MEQ. Our data demonstrated that high dose of MEQ (275 mg/kg) apparently led to tissue impairment combined with imbalance of redox in liver. In liver and spleen samples, hydroxylation metabolites and desoxymequindox were detected, directly confirming the potential link of N→O group reduction metabolism with its organ toxicity. Moreover, up-regulation of JAK/STAT, SOCS family, tumor necrosis factor (TNF-α) and interleukin-6 (IL-6) were also observed in the high-dose group. Meanwhile, significant changes of oxidative stress indices in liver were observed in the high-dose group. As for NADPH subunit, the mRNA levels of many subunits were significantly up-regulated at low doses but down-regulated in a dose-dependent manner in liver and spleen, suggesting an involvement of NADPH in MEQ metabolism and ROS generation. In conclusion, we reported the dose-dependent long-term toxicity as well as the discussion of the potential mechanism and pathways of MEQ, which raised further awareness of its toxicity following with the dose change.
authors.affiliation: MOA Key Laboratory of Food Safety Evaluation/National Reference Laboratory of Veterinary Drug Residues (HZAU), Huazhong Agricultural University, Wuhan, Hubei 430070, PR China.
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.forename: Xian-Ju
authors.initials: XJ
authors.lastname: Huang
authors.forename: Awais
authors.initials: A
authors.lastname: Ihsan
authors.forename: Zhao-Ying
authors.initials: ZY
authors.lastname: Liu
authors.forename: Ling-Li
authors.initials: LL
authors.lastname: Huang
authors.forename: Hua-Hai
authors.initials: HH
authors.lastname: Zhang
authors.forename: Hong-Fei
authors.initials: HF
authors.lastname: Zhang
authors.forename: Wen
authors.initials: W
authors.lastname: Zhou
authors.forename: Qin
authors.initials: Q
authors.lastname: Liu
authors.forename: Xi-Juan
authors.initials: XJ
authors.lastname: Xue
authors.forename: Zong-Hui
authors.initials: ZH
authors.lastname: Yuan
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D053612:Janus Kinases / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011810:Quinoxalines / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013154:Spleen / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: C545385:Mequindox; D011810:Quinoxalines; D050791:STAT Transcription Factors; D053612:Janus Kinases