Abstract:
:The diabetogenic agent alloxan is a triketone that selectively destroys pancreatic beta cells. To investigate the importance of the triketone structure of alloxan for its cytotoxic potency, alloxan was compared with ninhydrin, also a triketone, and the amino derivative of alloxan uramil, which is not a triketone, because the 5-keto group of the alloxan is replaced by an amino group. Both compounds are cytotoxic but not diabetogenic. Ninhydrin was capable of generating cytotoxic reactive oxygen species (ROS) through redox cycling with dithiols, and uramil could also generate cytotoxic ROS. Both ninhydrin and uramil could not redox cycle with glutathione (GSH) and were not selectively toxic to beta cells; their structure does not allow selective cellular uptake via the GLUT2 glucose transporter. Thus, the results show that the 5-keto group in the pyrimidine ring structure of the triketone alloxan is crucially important for its ability to be selectively taken up into the beta cells via the specific glucose transporter GLUT2. The 5-keto group of the molecule enables redox cycling of alloxan through reaction with glutathione (GSH), thereby generating the cytotoxic ROS. Thus, the unique combination of these two properties confers on alloxan the beta cell-selective toxicity and diabetogenicity. Replacement of the 5-keto group by an amino group, as in uramil, abolishes selective beta cell toxicity because of the loss of the glucose analogue structure and the capability to generate ROS via redox cycling with GSH and cysteine.
journal_name
Antioxid Redox Signaljournal_title
Antioxidants & redox signalingauthors
Elsner M,Gurgul-Convey E,Lenzen Sdoi
10.1089/ars.2007.1816subject
Has Abstractpub_date
2008-04-01 00:00:00pages
691-9issue
4eissn
1523-0864issn
1557-7716journal_volume
10pub_type
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