Nonantibiotic Effects of Fluoroquinolones in Mammalian Cells.
Nonantibiotic Effects of Fluoroquinolones in Mammalian Cells.
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DOI：
10.1074/jbc.m115.671222
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发表时间：
2015-09-04
期刊：
影响因子：
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通讯作者：
Maher LJ 3rd
中科院分区：
文献类型：
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作者：
Badal S;Her YF;Maher LJ 3rd
背景：Fe(II)依赖的双加氧酶调节表观遗传控制、胶原成熟和HIF降解。结果：氟喹诺酮类抗生素可导致DNA和组蛋白高甲基化，抑制胶原蛋白羟化，抑制HIF基因翻译。结论：双加氧酶抑制可能是氟喹诺酮类药物肾毒性和肌腱病副反应的原因。意义：这项研究提示了氟喹诺酮类药物相关副作用的机制，以及这些抗生素作为HIF拮抗剂可能的新应用。氟喹诺酮类(FQ)是一种强大的广谱抗生素，其副作用包括肾脏损害和奇怪的肌腱病。这些毒性的病理机制还知之甚少。在这里，我们证明了FQ药物诺氟沙星、环丙沙星和恩诺沙星是强大的铁络合剂，可与临床上有用的铁络合剂去铁胺相媲美。我们发现FQ通过抑制α-酮戊二酸依赖的双加氧酶而导致表观遗传效应，这种双加氧酶需要铁作为辅助因子。经FQ处理的HEK293细胞检测到三种双加氧酶。在亚毫摩尔浓度下，这些抗生素分别抑制juonji结构域的组蛋白去甲基酶、Tet DNA去甲基酶和胶原蛋白4-羟基酶，导致甲基化的组蛋白和DNA积聚，并抑制胶原中的Pro羟化。这些作用可能解释了氟喹诺酮引起的肾毒性和肌腱病变。根据同样的推论，FQ对双加氧酶的抑制可以通过抑制缺氧诱导的转录因子脯氨酸羟化来稳定转录因子HIF-1α。与这一预测形成鲜明对比的是，FQ处理消除了HIF-1α蛋白。我们探索了这种意想不到的作用的可能机制，并表明FQ抑制HIF-1α基因的翻译。因此，FQ抗生素诱导全球表观遗传变化，抑制胶原成熟，并阻止HIF-1α积聚。我们认为这些机制可以解释与FQ抗生素相关的典型的肾脏毒性和特殊的肌腱病。
Background: Fe(II)-dependent dioxygenases regulate epigenetic control, collagen maturation, and HIF degradation. Results: Iron chelation by fluoroquinolone antibiotics results in DNA and histone hypermethylation, suppression of collagen prolyl hydroxylation, and inhibition of HIF mRNA translation. Conclusion: Dioxygenase inhibition may explain renal toxicity and tendinopathy side effects of fluoroquinolones. Significance: This study suggests mechanisms for obscure fluoroquinolone-associated side effects and possible novel applications of these antibiotics as HIF antagonists. Fluoroquinolones (FQ) are powerful broad-spectrum antibiotics whose side effects include renal damage and, strangely, tendinopathies. The pathological mechanisms underlying these toxicities are poorly understood. Here, we show that the FQ drugs norfloxacin, ciprofloxacin, and enrofloxacin are powerful iron chelators comparable with deferoxamine, a clinically useful iron-chelating agent. We show that iron chelation by FQ leads to epigenetic effects through inhibition of α-ketoglutarate-dependent dioxygenases that require iron as a co-factor. Three dioxygenases were examined in HEK293 cells treated with FQ. At sub-millimolar concentrations, these antibiotics inhibited jumonji domain histone demethylases, TET DNA demethylases, and collagen prolyl 4-hydroxylases, leading to accumulation of methylated histones and DNA and inhibition of proline hydroxylation in collagen, respectively. These effects may explain FQ-induced nephrotoxicity and tendinopathy. By the same reasoning, dioxygenase inhibition by FQ was predicted to stabilize transcription factor HIF-1α by inhibition of the oxygen-dependent hypoxia-inducible transcription factor prolyl hydroxylation. In dramatic contrast to this prediction, HIF-1α protein was eliminated by FQ treatment. We explored possible mechanisms for this unexpected effect and show that FQ inhibit HIF-1α mRNA translation. Thus, FQ antibiotics induce global epigenetic changes, inhibit collagen maturation, and block HIF-1α accumulation. We suggest that these mechanisms explain the classic renal toxicities and peculiar tendinopathies associated with FQ antibiotics.