Deprecated: Implicit conversion from float 213.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534
Deprecated: Implicit conversion from float 213.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534
Deprecated: Implicit conversion from float 213.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534
Warning: imagejpeg(C:\Inetpub\vhosts\kidney.de\httpdocs\phplern\26205818
.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Biol+Chem
2015 ; 290
(36
): 22287-97
Nephropedia Template TP
gab.com Text
Twit Text FOAVip
Twit Text #
English Wikipedia
Nonantibiotic Effects of Fluoroquinolones in Mammalian Cells
#MMPMID26205818
Badal S
; Her YF
; Maher LJ 3rd
J Biol Chem
2015[Sep]; 290
(36
): 22287-97
PMID26205818
show ga
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
?-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-1? by inhibition of the oxygen-dependent
hypoxia-inducible transcription factor prolyl hydroxylation. In dramatic contrast
to this prediction, HIF-1? protein was eliminated by FQ treatment. We explored
possible mechanisms for this unexpected effect and show that FQ inhibit HIF-1?
mRNA translation. Thus, FQ antibiotics induce global epigenetic changes, inhibit
collagen maturation, and block HIF-1? accumulation. We suggest that these
mechanisms explain the classic renal toxicities and peculiar tendinopathies
associated with FQ antibiotics.
free
free
free
