Relative importance of cellular uptake and reactive oxygen species for the toxicity of alloxan and dialuric acid to insulin-producing cells.
The diabetogenic agent alloxan is selectively accumulated in insulin-producing cells through uptake via the GLUT2 glucose transporter in the plasma membrane. In the presence of intracellular thiols, especially glutathione, alloxan generates "reactive oxygen species" (ROS) in a cyclic reaction between this substance and its reduction product, dialuric acid. The cytotoxic action of alloxan is initiated by free radicals formed in this redox reaction. Autoxidation of dialuric acid generates superoxide radicals (O(2)(*-)) and hydrogen peroxide (H(2)O(2)), and finally hydroxyl radicals ((*)OH). Thus, while superoxide dismutase (SOD) only reduced the toxicity, catalase, in particular in the presence of SOD, provided complete protection of insulin-producing cells against the cytotoxic action of alloxan and dialuric acid due to H(2)O(2) destruction and the prevention of hydroxyl radical ((*)OH) formation, indicating that it is the hydroxyl radical ((*)OH) which is the ROS ultimately responsible for cell death. After selective accumulation in pancreatic beta cells, which are weakly protected against oxidative stress, the cytotoxic glucose analogue alloxan destroys these insulin-producing cells and causes a state of insulin-dependent diabetes mellitus through ROS-mediated toxicity in rodents and in other animal species, which express this glucose transporter isoform in their beta cells.
Elsner
Matthias
M
Institute of Clinical Biochemistry, Hannover Medical School, 30623 Hannover, Germany.
Gurgul-Convey
Ewa
E
Lenzen
Sigurd
S
D000496:Alloxan / Q000494:pharmacology*; D000818:Animals; D001463:Barbiturates / Q000378:metabolism / Q000494:pharmacology*; D002374:Catalase / Q000378:metabolism; D002470:Cell Survival; D018076:DNA, Complementary / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism; D005609:Free Radicals; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D010100:Oxygen; D051381:Rats; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D001463:Barbiturates; D018076:DNA, Complementary; D005609:Free Radicals; D007328:Insulin; D017382:Reactive Oxygen Species; D013481:Superoxides; C004718:dialuric acid; D000496:Alloxan; D002374:Catalase; D013482:Superoxide Dismutase; D010100:Oxygen