NITRIC-OXIDE GENERATION FROM STREPTOZOTOCIN

Streptozotocin (STZ), a diabetogenic agent, is thought to damage pancreatic beta-cells by activating immune mechanisms and by alkylating DNA. In the present study, we demonstrated that STZ can produce nitric oxide (NO), a bioregulatory and cytotoxic molecule. When STZ was dissolved in a sodium phosphate buffer (50 mM, pH 7.4) and irradiated with a 22 W circular fluorescent light, nitrite and nitrate, stable oxidation products of NO, were produced. The wavelengths of light most responsible for the photo-decomposition were 300-310 nm and 410-420 nm. When a mixture of reduced hemoglobin and STZ was irradiated with UV light (280-320 nm), hemoglobin underwent characteristic NO-dependent spectral changes. STZ relaxed deendothelialized aortic strips only in the presence of light. STZ/light-dependent relaxation was attenuated by reduced hemoglobin. These results indicated photoinduced NO production from STZ. NO generation depended on the concentration of STZ, the duration of irradiation, and the distance between sample and light source. In acidic conditions, NO production from STZ was spontaneous even in the dark. Light-independent NO generation was augmented by increasing acidity, and markedly diminished in a D2O-based buffer, indicating the involvement of protons in the mechanism of STZ decomposition in acid. These results imply the usefulness of STZ as an NO-generating reagent, and indicate that direct NO-generation may be a mechanism of STZ toxicity in diabetogenesis.