NITRIC-OXIDE GENERATION FROM STREPTOZOTOCIN

Streptozotocin (STZ), a diabetogenic agent, is thought to damage pancr eatic beta-cells by activating immune mechanisms and by alkylating DNA . In the present study, we demonstrated that STZ can produce nitric ox ide (NO), a bioregulatory and cytotoxic molecule. When STZ was dissolv ed 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 responsi ble 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 (2 80-320 nm), hemoglobin underwent characteristic NO-dependent spectral changes. STZ relaxed deendothelialized aortic strips only in the prese nce of light. STZ/light-dependent relaxation was attenuated by reduced hemoglobin. These results indicated photoinduced NO production from S TZ. NO generation depended on the concentration of STZ, the duration o f irradiation, and the distance between sample and light source. In ac idic conditions, NO production from STZ was spontaneous even in the da rk. Light-independent NO generation was augmented by increasing acidit y, and markedly diminished in a D2O-based buffer, indicating the invol vement 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.