Ciprofloxacin (Cipro and Levaquin), a fluoroquinolone, is the third most commonly used antibiotic, and inhibits mitochondrial DNA (mtDNA) synthesis, affecting cellular growth and differentiation. It does this by inhibiting the mtDNA’s ability to relax from a supercoiled state or mtDNA topology. Topology is the ability to twist, bend or coil. mtDNA topology homeostasis (equilibrium) is required for proper gene expression, which controls a cells ability to replicate and differentiate.
Note: Fluoroquinolones have fluoride as a central part of the drug. Fluoride is a known neurotoxin, and drugs with an attached fluoride allow them to penetrate more effectively through cell membranes and very sensitive tissues like the blood-brain-barrier.
The severe side effects of ciprofloxacin and other fluoroquinolones include “tendinopathies” such as TENDON RUPTURE, JOINT INFLAMMATION, MUSCLE WEAKNESS, CENTRAL AND PERIPHERAL NEUROPATHIES, EPILEPSY and psychological symptoms such as DEPRESSION, possibly due to enhanced oxidative stress. The reduction in overall mtDNA and mitochondrial transcription (copying a gene’s DNA sequence) caused by the altered topology of mtDNA might result in severe dysregulation of the electron transport chain’s (ETC) protein complexes, leading to (ECT) dysfunction, reduced ATP (energy) production and causing the observed enhanced oxidative stress (above pathologies).
Ciprofloxacin (Cipro and Levaquin) has also been reported to interfere with spermatogenesis, brain development, bone mineralization, as well as to induce renal toxicity and heart arrhythmia. While the molecular mechanisms of these adverse effects are yet unclear, mitochondria play a central role in all of these physiological processes, making mitochondrial impairment a likely culprit for the disturbed cellular physiology.
Ciprofloxacin (Cipro and Levaquin) plasma concentrations in patients after a single oral administration reach normally around 2 μg/ml and after intravenous injection 6 μg/ml and an up to a 20-fold accumulation of ciprofloxacin in tissue has been reported. We found the inhibition of mtDNA maintenance starting from 40 μg/ml ciprofloxacin, a concentration that might be well exceeded in patients with altered pharmacokinetics due to OBESITY, AGE, KIDNEY IMPAIRMENT or simultaneous CORTICOSTEROID USE, who experience the adverse side effects of fluoroquinolones most frequently.
The fact that Top2β (the enzyme affected by Cipro and Levaquin) exists in brain mitochondria at far higher levels compared to other tissues, suggesting a specific demand for mtDNA topology regulation in neural cells, could indicate that the tissue has a higher sensitivity against inhibition that should be investigated.
As a conclusion, the maintenance of topological homeostasis in mitochondria is required for gene expression and replication of mtDNA as it is for other genomes. Our results identified mtDNA as a key target for ciprofloxacin-induced adverse effects through inhibition of Top2. As fluoroquinolone antibiotics are widely used and effective drugs against a number of important bacterial pathogens, their dosage, systemic enrichment, and side-effects should be reviewed in the mitochondrial context, and their clinical use should be considered with great care.