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J Biol Chem. 2015 Sep 4;290(36):22287-97. doi: 10.1074/jbc.M115.671222. Epub 2015 Jul 23.

Nonantibiotic Effects of Fluoroquinolones in Mammalian Cells.

Author information

1
From the Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905.
2
From the Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905 Maher@mayo.edu.

Abstract

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.

KEYWORDS:

antibiotic action; collagen; dioxygenase; epigenetics; fluoroquinolone; iron

PMID:
26205818
PMCID:
PMC4571980
DOI:
10.1074/jbc.M115.671222
[Indexed for MEDLINE]
Free PMC Article

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