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Mechanism of adrenocortical toxicity induced by quinocetone and its bidesoxy-quinocetone metabolite in porcine adrenocortical cells in vitro

Author:
Wang, Xu, Wan, Dan, Ihsan, Awais, Liu, Qianying, Cheng, Guyue, Li, Juan, Liu, Zhenli, Yuan, Zonghui
Source:
Food and chemical toxicology 2015 v.84 pp. 115-124
ISSN:
0278-6915
Subject:
aldosterone, antibiotics, apoptosis, biosynthesis, cytotoxicity, enzymes, messenger RNA, metabolites, mitochondria, necrosis, oxidative stress, secretion, steroid hormones, swine, toxicology
Abstract:
Quinocetone (QCT) is a new feeding antibacterial agent in the QdNOs family. The mechanism of its adrenal toxicity is far from clear. This study was conducted to estimate the adrenal cell damage induced by QCT and its bidesoxy-quinocetone (B-QCT) metabolite and to further investigate their mechanisms. Following doses of QCT increasing from 5 to 50 μM, cell apoptosis and necrosis, mitochondrial dysfunction and redox imbalance were observed in porcine adrenocortical cells. The mRNA levels of the six components of intermediary enzymes and the adrenal renin-angiotensin-aldosterone system (RAAS) displayed a dysregulation induced by QCT, indicating that QCT might influence aldosterone secretion not only through the upstream of the production but also through the downstream of the adrenal RAAS pathway. In contrast, B-QCT had few toxic effects on the cell apoptosis, mitochondrial dysfunction and redox imbalance. Moreover, LCMS-IT-TOF analysis showed that no desoxy metabolites of QCT were found in either cell lysate or supernatant samples. In conclusion, we reported on the cytotoxicity in porcine adrenocortical cells exposed to QCT via oxidative stress, which raised awareness that its toxic effects resulted from N→O groups, and its toxic mechanism might involve the interference of the steroid hormone biosynthesis pathway.
Agid:
5419768