Mechanism of the protective activity of ICRF-187 against alloxan-induced diabetes in mice.
ICRF-187, (+)-1,2-bis(3,5-dioxopiperazine-1-yl)propane, has been shown to protect against alloxan diabetes (el-Hage et al., 1981). Since alloxan-induced pancreatic beta cell damage is thought to be mediated through the generation of highly reactive oxygen radicals by a metal catalyzed reaction involving both superoxide anion and hydrogen peroxide, in the present study the protective activity of ICRF-187 was compared with that of free radical scavengers, microsomal enzyme inhibitors and chelating agents. The free radical scavengers DMSO, vitamin E and WR2721 markedly reduced alloxan-induced hyperglycemia. ICRF-187 was found not to interact with superoxide anions, and there is no evidence to indicate that any of the known biological effects of ICRF-187 are mediated through free radical scavenging activity. SKF-525 and cimetidine, known inhibitors of drug metabolizing enzymes, also protected against the diabetogenic action of alloxan. Since it was found that ICRF-187 did not alter hexobarbital sleeping time, this compound must protect by a mechanism other than microsomal enzyme inhibition. Since the chelating agents EDTA and DETAPAC were found to protect against alloxan diabetes, ICRF-187 or its hydrolytic products, which are structurally similar to EDTA, could function as chelating agents. Transitional metals such as iron, zinc and copper were found to bind preferentially to a hydrolysis product of ICRF-187. Chelation of iron by ICRF-187 or its hydrolytic products could decrease in vivo formation of reactive oxygen radicals and provide a means for protecting against chronic anthracycline cardiotoxicity and alloxan diabetes.
D000496:Alloxan / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D002927:Cimetidine / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000517:prevention & control*; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D006591:Hexobarbital / Q000494:pharmacology; D006943:Hyperglycemia / Q000517:prevention & control; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010879:Piperazines / Q000494:pharmacology*; D011335:Proadifen / Q000494:pharmacology; D011929:Razoxane / Q000378:metabolism / Q000494:pharmacology*; D012890:Sleep / Q000187:drug effects; D013237:Stereoisomerism; D013482:Superoxide Dismutase / Q000378:metabolism
D001786:Blood Glucose; D002614:Chelating Agents; D010879:Piperazines; D011929:Razoxane; D000496:Alloxan; D002927:Cimetidine; D011335:Proadifen; D006591:Hexobarbital; D013482:Superoxide Dismutase; D004121:Dimethyl Sulfoxide