Volume 50, Issue 6:

MINIREVIEW


The Mechanism of Alloxan and Streptozotocin Action in B Cells of the Rat Pancreas

T. SZKUDELSKI

Department of Animal Physiology and Biochemistry, University of Agriculture, Poznan, Poland

Received November 2, 2000
Accepted March 20, 2001


Summary
Alloxan and streptozotocin are widely used to induce experimental diabetes in animals. The mechanism of their action in B cells of the pancreas has been intensively investigated and now is quite well understood. The cytotoxic action of both these diabetogenic agents is mediated by reactive oxygen species, however, the source of their generation is different in the case of alloxan and streptozotocin. Alloxan and the product of its reduction, dialuric acid, establish a redox cycle with the formation of superoxide radicals. These radicals undergo dismutation to hydrogen peroxide. Thereafter highly reactive hydroxyl radicals are formed by the Fenton reaction. The action of reactive oxygen species with a simultaneous massive increase in cytosolic calcium concentration causes rapid destruction of B cells. Streptozotocin enters the B cell via a glucose transporter (GLUT2) and causes alkylation of DNA. DNA damage induces activation of poly ADP-ribosylation, a process that is more important for the diabetogenicity of streptozotocin than DNA damage itself. Poly ADP-ribosylation leads to depletion of cellular NAD+ and ATP. Enhanced ATP dephosphorylation after streptozotocin treatment supplies a substrate for xanthine oxidase resulting in the formation of superoxide radicals. Consequently, hydrogen peroxide and hydroxyl radicals are also generated. Furthermore, streptozotocin liberates toxic amounts of nitric oxide that inhibits aconitase activity and participates in DNA damage. As a result of the streptozotocin action, B cells undergo the destruction by necrosis.


Key words
Alloxan Streptozotocin Pancreatic B cells Mechanism of action Diabetes

Reprint requests
T. Szkudelski, Department of Animal Physiology and Biochemistry, University of Agriculture, 60-637 Wolynska 35, Poznan, Poland.

 

PHYSIOLOGICAL RESEARCH
2001 by the Institute of Physiology,
Czech Academy of Sciences

ISSN 0862 - 8408

Issue 6