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. (3rd February 2016)

• Record Type: Journal Article
• Authors: Wang, Xu; Yang, Chunhui; Ihsan, Awais; Luo, Xun; Guo, Pu; Cheng, Guyue; Dai, Menghong; Chen, Dongmei; Liu, Zhenli; Yuan, Zonghui
• Is Part Of: Toxicology. Volume 341/343(2016)
• Page Start: 1
• Page End: 16
• Publication Date: 2016-02-03
• Subjects: ALD aldosterone -- ATF-1 activating transcription factor-1 -- cDNA complementary DNA -- CREB cyclic AMP response element binding protein -- CYA cyadox -- CYP11B1 11β-hydroxylase -- CYP11B2 aldosterone synthase -- DAB 3′, 3′-diaminobenzidine -- DMSO dimethyl sulfoxide -- dNTP deoxyribonucleoside triphosphate -- EDTA ethylene diamine tetraacetic acid -- EB ethidium bromide -- ELISA enzyme-linked immunosorbent assay -- GSH-Px glutathione peroxidase -- ITS+ Premix cell growth factor mixed medium -- LDH lactate dehydrogenase -- MEQ mequindox -- MDA malondialdehyde -- MTT 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide -- N1-desoxy QdNOs N1-desoxy quinoxaline 1, 4-dioxide derivatives -- N1-desoxy QCT N1-desoxy quinocetone -- N1-desoxy MEQ N1-desoxy mequindox -- N1-desoxy CYA N1-desoxy cyadox -- NGFIB the nerve growth factor-induced clone B (NR4A1) -- NURR1 the nuclear receptor related factor 1 (NR4A2) -- Nu-serum growth medium supplements -- OPC oligomeric proanthocyanidins -- PBS phosphate-buffered saline -- QCT quinocetone -- QdNOs quinoxaline 1, 4-dioxide derivatives -- RT-PCR reverse transcriptional polymerase chain reaction -- SF-1 steroidogenic factor-1 -- SOD superoxide dismutase; Quinoxaline -- Quinocetone -- Mequindox -- Cyadox -- Adrenal toxicity -- H295R cells -- Aldosterone; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2016.01.005
• Languages: English
• ISSNs: 0300-483X

Abstract

Graphical abstract: Highlights: N 1-QCT, N 1-MEQ and N 1-CYA showed more adrenal toxicity than other metabolites. N 1-desoxy QdNOs reduced expression of CYP11B1, CYP11B2 and transcription factors. OPC increased expression of transcription factors, including CYP11B1 and CYP11B2. OPC reduced adrenal toxicity induced by N 1-desoxy QdNOs. The results provided a mechanism of adrenal damage caused by QdNO metabolites. 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 N 1-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 N 1-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 N 1-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.