title: Effect of fluoroquinolones on mitochondrial function in pancreatic beta cells.
abstract: Hyper- and hypoglycaemias are known side effects of fluoroquinolone antibiotics, resulting in a number of fatalities. Fluoroquinolone-induced hypoglycaemias are due to stimulated insulin release by the inhibition of the KATP channel activity of the beta cell. Recently, it was found that fluoroquinolones were much less effective on metabolically intact beta cells than on open cell preparations. Thus the intracellular effects of gatifloxacin, moxifloxacin and ciprofloxacin were investigated by measuring NAD(P)H- and FAD-autofluorescence, the mitochondrial membrane potential, and the adenine nucleotide content of isolated pancreatic islets and beta cells. 100 μM of moxifloxacin abolished the NAD(P)H increase elicited by 20mM glucose, while gatifloxacin diminished it and ciprofloxacin had no significant effect. This pattern was also seen with islets from SUR1 Ko mice, which have no functional KATP channels. Moxifloxacin also diminished the glucose-induced decrease of FAD-fluorescence, which reflects the intramitochondrial production of reducing equivalents. Moxifloxacin, but not ciprofloxacin or gatifloxacin significantly reduced the effect of 20mM glucose on the ATP/ADP ratio. The mitochondrial hyperpolarization caused by 20mM glucose was partially antagonized by moxifloxacin, but not by ciprofloxacin or gatifloxacin. Ultrastructural analyses after 20 h tissue culture showed that all three compounds (at 10 and 100 μM) diminished the number of insulin secretory granules and that gatifloxacin and ciprofloxacin, but not moxifloxacin induced fission/fusion configurations of the beta cell mitochondria. In conclusion, fluoroquinolones affect the function of the mitochondria in pancreatic beta cells which may diminish the insulinotropic effect of KATP channel closure and contribute to the hyperglycaemic episodes.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Braunschweig, D-38106 Braunschweig, Germany.
authors.forename: Hany
authors.initials: H
authors.lastname: Ghaly
authors.affiliation: Institute of Clinical Biochemistry, Hannover Medical School, 30623 Hannover, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Jörns
authors.affiliation: Institute of Pharmacology and Toxicology, University of Braunschweig, D-38106 Braunschweig, Germany. Electronic address: i.rustenbeck@tu-bs.de.
authors.forename: Ingo
authors.initials: I
authors.lastname: Rustenbeck
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001372:Aza Compounds / Q000494:pharmacology*; D002478:Cells, Cultured; D002939:Ciprofloxacin / Q000494:pharmacology*; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism; D024841:Fluoroquinolones / Q000494:pharmacology*; D000077734:Gatifloxacin; D005947:Glucose / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D000077266:Moxifloxacin; D009249:NADP / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D064233:Sulfonylurea Receptors / Q000172:deficiency / Q000235:genetics
chemical_list: C577508:Abcc8 protein, mouse; D000900:Anti-Bacterial Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D064233:Sulfonylurea Receptors; D005182:Flavin-Adenine Dinucleotide; D009249:NADP; D002939:Ciprofloxacin; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D005947:Glucose; D000077734:Gatifloxacin; D000077266:Moxifloxacin
keywords: ATP; Fluoroquinolones; Gatifloxacin; K(ATP); Mitochondria; Moxifloxacin; NAD(P)H-fluorescence; Pancreatic beta cells; Rh123; Rhodamine 123; SUR; channel; fluorescence of NADH and NADPH combined; sensitive K(+) channel; sulfonylurea receptor