Ciprofloxacin impairs mitochondrial DNA replication initiation through inhibition of Topoisomerase 2, 2018, Goffart et al

Andy · Sep 2, 2018

Abstract
Maintenance of topological homeostasis is vital for gene expression and genome replication in all organisms. Similar to other circular genomes, also mitochondrial DNA (mtDNA) is known to exist in various different topological forms, although their functional significance remains unknown.

We report here that both known type II topoisomerases Top2α and Top2β are present in mammalian mitochondria, with especially Top2β regulating the supercoiling state of mtDNA. Loss of Top2β or its inhibition by ciprofloxacin results in accumulation of positively supercoiled mtDNA, followed by cessation of mitochondrial transcription and replication initiation, causing depletion of mtDNA copy number. These mitochondrial effects block both cell proliferation and differentiation, possibly explaining some of the side effects associated with fluoroquinolone antibiotics.

Our results show for the first time the importance of topology for maintenance of mtDNA homeostasis and provide novel insight into the mitochondrial effects of fluoroquinolones.
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Open access at https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gky793/5088042

mariovitali · Sep 2, 2018

Ciprofloxacin may cause DILI (Drug Induced Liver Injury).

Hepatotoxicity

Ciprofloxacin like other fluoroquinolones is associated with a low rate (1% to 3%) of serum enzyme elevations during therapy. These abnormalities are generally mild, asymptomatic and transient, resolving even with continuation of therapy. More importantly, ciprofloxacin has been linked to rare, but occasionally severe and even fatal cases of acute liver injury. The time to onset is typically short (2 days to 2 weeks) and the presentation is often abrupt with nausea, fatigue and abdominal pain, followed by dark urine and jaundice. The pattern of serum enzyme elevations can be either hepatocellular or cholestatic; cases with the shorter times to onset usually being more hepatocellular with markedly elevated ALT levels, and occasionally with rapid worsening of prothrombin time and early signs of hepatic failure. The onset of illness also may occur a few days after the medication is stopped. Cases with a cholestatic pattern of enzymes may run a prolonged course, but are usually self-limiting. Nevertheless, chronic cholestasis and vanishing bile duct syndrome have been reported with ciprofloxacin and other fluoroquinolones. Finally, the enzyme pattern can be initially hepatocellular and then evolve during the course of illness from a hepatocellular into a mixed or cholestatic pattern. Many (but not all) cases have had allergic manifestations with fever, rash and eosinophilia. Autoantibodies are usually not present.

Likelihood score: B (likely cause of clinically apparent liver injury).
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https://livertox.nlm.nih.gov/Ciprofloxacin.htm

Interestingly, Coxsackie B, EBV, Cytomegalovirus, HHV-6, Parvovirus B19 can also cause Liver Injury.

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Ciprofloxacin impairs mitochondrial DNA replication initiation through inhibition of Topoisomerase 2, 2018, Goffart et al

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Ciprofloxacin impairs mitochondrial DNA replication initiation through inhibition of Topoisomerase 2, 2018, Goffart et al

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