Adverse Effects of Fluoroquinolones - DNA Effects

DNA Effects

The fluoroquinolones exert their therapeutic effects by interfering with bacterial DNA replication by inhibiting an enzyme complex called DNA gyrase. Research has indicated that fluoroquinolones at therapeutically used doses have little effect on enzymes involved in DNA replication in mammalian cells including human cells; however, not all subtypes of eucaryotic topoisomerases have been routinely studied in clinical studies. In vitro studies in human fibroblast cells have shown that nalidixic acid can impair repair type DNA synthesis at a relatively low dosage (5 ug/ml), but this effect is seen only at very high doses (at least 50 ug/ml) of other quinolones (ciprofloxacin, norfloxacin, and ofloxacin) tested. Fluoroquinolones increase the uptake of deoxyuridine, uridine, and thymidine into the DNA of human lymphocytes and decrease pyrimidine production. A reduction in leucine occurs. With some quinolones, these effects appear to occur at therapeutic dose levels. Quinolones also appear to effect the growth of eucaryotic cells and HeLa cells. However, relatively high doses of quinolones (20 ug/ml) are required to impair eucaryotic cell growth. At doses that are achievable in therapeutic dosing of (5 ug/ml), a 50% reduction in lymphocyte immunogloblin production occurs. DNA damage such as strand breaks, occurs only at extremely high doses of fluoroquinolones (above 100 ug/ml). DNA polymerase a, topoisomerase I, topoisomerase II, and mitochondrial function are inhibited only at high doses of quinolones above the dosages that would be seen in clinical practice. Some quinolones have been shown to be capable of causing injury to the chromosome of eukaryotic cells. As such, some fluoroquinolones may cause injury to the chromosome of eukaryotic cells. There is some debate in the medical literature as to whether these DNA effects are to be considered one of the mechanisms of action concerning some of the severe ADRs and toxicities experienced by some patients following fluoroquinolone therapy. It has been speculated that the effects of fluoroquinolones on human eukaryotic topoisomerases have potential to cause cytotoxicity. Fluoroquinolones may have the potential to cause clastogenicity and the induction of micronuclei. Retinal pigment epithelial cells are critical to the functioning of the eye and are involved in many eye diseases. In one study, DNA damage to RPE cells was observed with Sparfloxacin.