A number of N-nitroso compounds in the environment damage the beta cell of the pancreas. Why these chemicals have a tropism for the pancreatic beta cell is undetermined. Moreover, it is unknown how they enter and injure the cell. Do beta cells preferentially metabolize and accumulate more of these chemicals than other cell types? What is the sequence of events leading to cell death and can they be prevented by artificial manipulation? The objective of this proposal is to elucidate and compare the interaction of two structurally similar N-nitroso compounds with beta cells and pancreatic fibroblasts in vitro. We will define how the chemicals enter the beta cell and damage its membranes, a process that is thought to result in cell death. Streptozotocin (SZ) is a well known experimental diabetogenic agent comprised of glucose and methylnitrosourea. Chlorozotocin (CLZ), composed structurally of glucose and chloroethylnitrosourea, is a cancer chemotherapeutic agent in man and is also diabetogenic in rodents. Using islet cells isolated from rat, we will determine whether 1) the glucose moeity interacts with a specific carbohydrate receptor on the plasma membrane of the beta cell; 2) uptake of chemicals is either a passive event or an active process dependent upon metabolism and a carrier transport mechanism for glucose; and 3) chemicals cause damage to the plasma membrane and stimulate release of oxygen free radicals from islet cells. To define the species of radical important in injury, we will add specific scavengers of free radicals to cultures in an attempt to prevent SZ and CLZ-induced cytotoxicity. Damage to the beta cell will be measured by radioimmunoassay for insulin and release of 75Selenium-methionine from membranes. Because N-nitroso compounds such as Vacor, a rodenticide that is diabetogenic in man, are similar in chemical composition to both SZ and CLZ, it is important to determine what structural moeities cause cell damage. We will address this question using non-nitrosated analogs of SZ and CLZ and analogs with removal of methyl and chloroethyl groups. Our approaches are unique and should define not only how and why two diabetogenic chemicals cause damage to the beta cell, but what structural components elicit cell injury.
| Mossman, B T; Wilson, G L; Craighead, J E (1985) Chlorozocin. A diabetogenic analogue of streptozocin with dissimilar mechanisms of action on pancreatic beta cells. Diabetes 34:602-10 |
