Fusidic acid suppresses nitric oxide toxicity in pancreatic islet cells.
Earlier preclinical and clinical trials indicate that fusidic acid, a triterpenoid compound originally described as an antimicrobial drug may protect islet beta cells from destruction in type I (insulin-dependent) diabetes mellitus. Since nitric oxide appears to be an important mediator of inflammatory islet cell death we analyzed whether fusidic acid interferes with nitric oxide production or action. We report here that fusidic acid dose-dependently inhibits lysis of isolated islet cells by activated macrophages, a process mediated by nitric oxide. In the presence of 100 microM fusidic acid macrophage-mediated islet cell lysis was reduced from 52.5 to 1.7% (P < 0.001). Fusidic acid only slightly affected macrophage function and did not inhibit the release of nitric oxide. We therefore tested whether fusidic acid suppresses nitric oxide toxicity in target cells. Isolated islet cells were exposed to the nitric oxide donor nitroprusside which led to DNA strand breaks and plasma membrane lysis. DNA strand breaks were reduced from 54.6 to 34.9% (P < 0.001) in the presence of 100 microM fusidic acid and cell lysis was reduced from 60.1 to 27.5% with 100 microM (P < 0.001). In the presence of 500 microM fusidic acid DNA strand breaks and cell lysis were reduced further to 27.1 and 10.7%, respectively (P < 0.001). No protection by fusidic acid was observed when cells were exposed to oxygen radicals or the alkylating beta cell toxin streptozotocin. The suppression of nitric oxide toxicity by fusidic acid was not due to its known inhibitory action on protein biosynthesis and thus represents a hitherto unknown activity of this drug.
Burkart
V
V
Diabetes Research Institute, University of Düsseldorf, Germany.
Bellmann
K
K
Hartmann
B
B
Heller
B
B
Imai
Y
Y
Kolb
H
H
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002701:Chloramphenicol / Q000494:pharmacology; D004347:Drug Interactions; D005672:Fusidic Acid / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000633:toxicity; D014176:Protein Biosynthesis; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin / Q000494:pharmacology
D009569:Nitric Oxide; D005672:Fusidic Acid; D013311:Streptozocin; D002701:Chloramphenicol