Fluoroquinolones are a class of widely
prescribed antibiotics with
a broad range of activity against Gram-positive, Gram-negative, and
some atypical microbes. Unfortunately, these drugs are associated
with significant adverse events including neuropathy, tendinopathy,
cardiac rhythm abnormalities, and mental health side effects. The
mechanism by which fluoroquinolones cause many of these toxicities
is unknown. The antibacterial mechanism of action involves disruption
of the catalytic mechanism of type-II topoisomerases in bacteria,
namely topoisomerase IV and DNA gyrase. Fluoroquinolones inhibit the
ability of the enzymes to ligate cleaved DNA and result in single-
and double-stranded DNA breaks. Thus, there is an interest in investigating
whether human topoisomerase II is involved in mediating the adverse
events associated with quinolones. Previous studies demonstrate some
response of human topoisomerase IIα and IIβ to high levels
of ciprofloxacin. However, it is not clear whether the concentration
of ciprofloxacin utilized in those studies corresponds to concentrations
that would be routinely achievable in patients. Therefore, this study
set out to examine three clinically relevant fluoroquinolones along
with two older agents to determine whether these compounds display
activity against topoisomerase IIα and IIβ at drug concentrations
that more closely approximate typical patient plasma values. On the
basis of our evidence, none of the quinolones studied were able to
poison DNA cleavage by either human enzyme. Ciprofloxacin, desethylene-ciprofloxacin,
and the recently removed from market gemifloxacin were able to inhibit
topoisomerase II-mediated DNA relaxation at concentrations of 200–300
μM. On the basis of these data, we propose that human topoisomerase
II is not likely to be the main cause of these adverse events and
that additional targets need to be identified to clarify the mechanisms
underlying quinolone toxicities.