title: Nonantibiotic Effects of Fluoroquinolones in Mammalian Cells.
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.
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Sujan
authors.initials: S
authors.lastname: Badal
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Yeng F
authors.initials: YF
authors.lastname: Her
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905 Maher@mayo.edu.
authors.forename: L James
authors.initials: LJ
authors.lastname: Maher
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D002939:Ciprofloxacin / Q000737:chemistry / Q000494:pharmacology; D019175:DNA Methylation / Q000187:drug effects; D003676:Deferoxamine / Q000737:chemistry / Q000494:pharmacology; D049308:Dioxygenases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000077422:Enrofloxacin; D044127:Epigenesis, Genetic / Q000187:drug effects* / Q000235:genetics; D024841:Fluoroquinolones / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D008745:Methylation / Q000187:drug effects; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D015394:Molecular Structure; D009643:Norfloxacin / Q000737:chemistry / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D018841:HSP90 Heat-Shock Proteins; D006657:Histones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007502:Iron Chelating Agents; D000077422:Enrofloxacin; D002939:Ciprofloxacin; D007501:Iron; D049308:Dioxygenases; D048055:Mitogen-Activated Protein Kinase 8; D003676:Deferoxamine; D009643:Norfloxacin
keywords: antibiotic action; collagen; dioxygenase; epigenetics; fluoroquinolone; iron