Alloxan has been used as a diabetogenic agent to induce diabetes. It selectively induces pancreatic beta-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 beta-cell is at least in part through proteasome inhibition. (C) 2017 Elsevier Inc. All rights reserved.