Diabetogenic agent alloxan is a proteasome inhibitor

Alloxan has been used as a diabetogenic agent to induce diabetes. It selectively induces pancreatic β-cell death. The specific toxicity, however, is not fully understood. In this study, we observed the effect of alloxan on proteasome function. We found that alloxan caused the accumulation of ubiquitinated proteins in NRK cells through the inhibition of the proteolytic activities of the proteasome. Biochemistry experiments with purified 26S and 20S proteasomes revealed that alloxan directly acts on the chymotrypsin- and trypsin-like peptidase activities. These results demonstrate that alloxan is a proteasome inhibitor, which suggests that its specific toxicity toward β-cell is at least in part through proteasome inhibition. - Highlights: • Alloxan inhibits the clearance of ubiquitinated proteins. • Alloxan inhibits the clearance of recombinant proteasome substrate GFP-CL1. • Alloxan inhibits the peptidase activities of the proteasome in the NRK cell nuclear extract. • Alloxan inhibits the proteasome dependent degradation of GST-Sp1 in NRK cell nuclear extract. • Alloxan inhibits the peptidase activities of the purified 26S and 20S proteasomes.