Nitric oxide generation from streptozotocin ¹

Abstract

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 photo-induced 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.

Dynamic O-GlcNAcylation and its roles in the cellular stress response and homeostasis

“…STZ has also been widely used, but only inhibits O-GlcNAcase at very high concentrations (Toleman et al 2006;Gao et al 2000;Liu et al 2002;Okuyama and Yachi 2001;Roos et al 1998). It is important to note that STZ is also a DNAalkylating agent and can release nitric oxide, making it difficult to determine whether the observed effects are due to O-GlcNAcase inhibition or STZ toxicity (Kwon et al 1994). Alloxan has been suggested to inhibit O-GlcNAcase (Lee et al 2006), but has been reported to also inhibit OGT and as such should be used with extreme caution Macauley et al 2005).…”

Protective effects of fermented ginseng on streptozotocin-induced pancreatic β-cell damage through inhibition of NF-κB

“…Whereas STZ induced nitrite generation in pancreas ß-cells, was attenuated by FG. Much evidence supports the hypothesis that high-output NO by iNOS provokes deleterious consequences in inflammatory diseases (3)(4)(5)23). The ability of FG to attenuate STZ-induced ß-cell damage was demonstrated by modulating the activity of immune response.…”

“…In the STZ-induced diabetic model, hyperglycemia arises from the irreversible destruction of pancreatic ß-cells through free radicals and nitric oxide (NO), causing degranulation and reduction of insulin secretion (3). Many effects of STZ on pancreatic islets are similar to those exerted by interleukin-1ß (IL-1ß) and some studies indicate that IL-1ß-induced islet injury as well as STZ-induced islet cytotoxicity are mediated by NO production (4,5).…”

Antioxidant Therapies for Hypolipidemia and Hyperglycemia

“…There was a significant increase in SOD, CAT and GSH-px It was reported that diabetic subjects are highly sensitive to oxidative stress (Pritchard et al, 1986). In STZ-diabetic animals, STZ generates nitric oxide, which is a powerful free radical oxidant (Kwon et al, 1994) resulting in an increase in blood glucose level. Several studies have documented the relationships between the increase of free radicals and blood glucose, lipid peroxidation as well as low-density lipoprotein in the progress of diabetes (Rabinovitch et al, 1996;Tanaka et al, 2002).…”