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.
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