title: High risk of adrenal toxicity of N1-desoxy quinoxaline 1,4-dioxide derivatives and the protection of oligomeric proanthocyanidins (OPC) in the inhibition of the expression of aldosterone synthetase in H295R cells.
abstract: Quinoxaline 1,4-dioxide derivatives (QdNOs) with a wide range of biological activities are used in animal husbandry worldwide. It was found that QdNOs significantly inhibited the gene expression of CYP11B1 and CYP11B2, the key aldosterone synthases, and thus reduced aldosterone levels. However, whether the metabolites of QdNOs have potential adrenal toxicity and the role of oxidative stress in the adrenal toxicity of QdNOs remains unclear. The relatively new QdNOs, cyadox (CYA), mequindox (MEQ), quinocetone (QCT) and their metabolites, were selected for elucidation of their toxic mechanisms in H295R cells. Interestingly, the results showed that the main toxic metabolites of QCT, MEQ, and CYA were their N1-desoxy metabolites, which were more harmful than other metabolites and evoked dose and time-dependent cell damage on adrenal cells and inhibited aldosterone production. Gene and protein expression of CYP11B1 and CYP11B2 and mRNA expression of transcription factors, such as NURR1, NGFIB, CREB, SF-1, and ATF-1, were down regulated by N1-desoxy QdNOs. The natural inhibitors of oxidant stress, oligomeric proanthocyanidins (OPC), could upregulate the expression of diverse transcription factors, including CYP11B1 and CYP11B2, and elevated aldosterone levels to reduce adrenal toxicity. This study demonstrated for the first time that N1-desoxy QdNOs have the potential to be the major toxic metabolites in adrenal toxicity, which may shed new light on the adrenal toxicity of these fascinating compounds and help to provide a basic foundation for the formulation of safety controls for animal products and the design of new QdNOs with less harmful effects.
authors.affiliation: National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Wuhan, Hubei 430070, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.affiliation: MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei 430070, China.
authors.forename: Chunhui
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Biosciences, COMSATS Institute of Information Technology, Sahiwal, Pakistan.
authors.forename: Awais
authors.initials: A
authors.lastname: Ihsan
authors.affiliation: Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, Hubei, China.
authors.forename: Xun
authors.initials: X
authors.lastname: Luo
authors.affiliation: Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, Hubei, China.
authors.forename: Pu
authors.initials: P
authors.lastname: Guo
authors.affiliation: Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, Hubei, China.
authors.forename: Guyue
authors.initials: G
authors.lastname: Cheng
authors.affiliation: MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei 430070, China.
authors.forename: Menghong
authors.initials: M
authors.lastname: Dai
authors.affiliation: Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, Hubei, China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Chen
authors.affiliation: Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, Hubei, China.
authors.forename: Zhenli
authors.initials: Z
authors.lastname: Liu
authors.affiliation: National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Wuhan, Hubei 430070, China; MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei 430070, China; Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, Hubei, China. Electronic address: yuan5802@mail.hzau.edu.cn.
authors.forename: Zonghui
authors.initials: Z
authors.lastname: Yuan
mesh_terms: D000307:Adrenal Gland Diseases / Q000139:chemically induced*; D000450:Aldosterone / Q000378:metabolism; D000975:Antioxidants / Q000494:pharmacology; D001711:Biotransformation; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006801:Humans; D018384:Oxidative Stress / Q000187:drug effects; D044945:Proanthocyanidins / Q000494:pharmacology*; D011810:Quinoxalines / Q000378:metabolism / Q000633:toxicity*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013252:Steroid 11-beta-Hydroxylase / Q000096:biosynthesis
chemical_list: D000975:Antioxidants; C545385:Mequindox; D044945:Proanthocyanidins; D011810:Quinoxalines; D012333:RNA, Messenger; C502851:quinocetone; D000450:Aldosterone; C020728:cyadox; C003282:quindoxin; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase
keywords: Adrenal toxicity; Aldosterone; Cyadox; H295R cells; Mequindox; Quinocetone; Quinoxaline