Influence of Nicotinamide and Pyridine Nucleotides on Streptozotocin and Alloxan Induced Pancreatic B Cell Cytotoxicity

Abstract

Pancreas from mice treated with 500 ing. per kilogram of nicotinamide intraperitoneally fifteen minutes before 200 nig. per kilogram of streptozotocin intravenously showed mostly unaltered islet B cells after eight, eighteen or fortyeight hours. Mice pretreated with 1,500 mg. per kilogram of either NAD, NADP or NADPH intraperitoneally showed almost no B cell lesions at eight hours. At eighteen hours some B cell necrohiosis was observed but of lesser extent than that seen after streptozotocin alone at eight hours. At forty-eight hours B cells showed diffuse, uniform necrobiosis only slightly less extensive than that seen in the group treated with streptozotocin alone. Pretreatment of mice with 500 mg. per kilogram nicotinamide intraperitoneally fifteen minutes before 100 mg. per kilogram alloxan intravenously failed to alter the extent of islet B cell lesions at eighteen hours. When the dosage of nicotinamide administered was increased to 1,000 mg. per kilogram and the time of pretreatment at this dose level increased to sixty minutes there was a slight decrease in the extent of B cell necrosis. Islets from rats pretreated with 1,000 mg. per kilogram nicotinamide intravenously sixty minutes prior to alloxan also showed a general lack of protective influence. Under the same conditions nicotinamide completely protected rats against the B cell cytotoxicity of streptozotocin. These findings demonstrate the almost specific protective action of nicotinamide against streptozotocin-induced B cell necrosis. While pyridine nucleotides slowed its development they did not prevent B cell necrosis after streptozotocin. The dissimilarity in the action of nicotinamide and pyridine nucleotides makes doubtful the view that streptozotocin-induced B cell necrosis is mediated via lowering of cellular content of NAD or other pyridine nucleotides below critical levels. The minimal protection afforded by nicotinamide against alloxan-induced B cell necrosis, as contrasted with its effectiveness against streptozotocin, confirms the view that the basic mechanisms of action of these drugs are different despite comparable selective B cell cytotoxicity.

The synthesis of [14C]streptozotocin and its distribution and excretion in the rat

“…142 and mode of action of streptozotocin has not been satisfactorily elucidated. In an attempt to explain the mechanism of action it has been suggested that diabetogenic activity of streptozotocin is mediated through its ability to lower pancreatic NAD+ concentrations significantly (Schein et al, 1967;Schein & Loftus, 1968;Schein & Bates, 1968;Junod et al, 1969;Ho & Hashim, 1972;Lazarus & Shapiro, 1973). This postulate is based on the observation that nicotinamide given either 10min before or up to 2h after streptozotocin prevents the development of diabetes (Dulin & Wyse, 1969a,b;Stauffacher et al, 1970;Lazarus & Shapiro, 1973).…”

Streptozotocin Diabetes CORRELATION WITH EXTENT OF DEPRESSION OF PANCREATIC ISLET NICOTINAMIDE ADENINE DINUCLEOTIDE

“…However, recent work indicates that only when nicotinamide is administered before alloxan is the pancreatic islet protected, whereas nicotinamide administered up to 60 min after streptozotocin still has an antagonistic effect (27). In addition, the study of Lazarus and Shapiro has shown a failure of nicotinamide to prevent beta cell destruction by alloxan in the mouse (19). The temporal development of diabetes is similar with both alloxan and streptozotocin.…”

“…4) To explain the relative ineffectiveness of MNU as a diabetogenic agent, a comparative study of drug distribution of streptozotocin and MNU was performed. To avoid possible contamination of the pancreas and other (2,4) and is specific in its protective action against streptozotocin-induced diabetes (2,18 (19). They base their conclusion on the finding that intraperitoneally administered NAD only partially prevented streptozotocin-induced diabetes, as determined by histologic examination.…”

Effects of streptozotocin in vitro on proinsulin biosynthesis, insulin release and ATP content of isolated rat islets of Langerhans

“…In characterizing the effects of streptozotocin, it was of interest to know whether nicotinamide or methylnicotinamide could protect against the streptozotocin-induced inhibition of proinsulin and total protein synthesis, just as they have been reported to protect the insulin release capability [17][18][19][20][21][22][23][24]. In one experiment, 10 mM nicotinamide or 4 mM methyl nicotinamide were included in the incubation medium with or without 2.2 mM streptozotocin.…”

“…Certainly, the administration of nicotinamide, a precursor of NAD in many tissues, protects against the diabetogenic effects of subsequently administered streptozotocin [17][18][19][20][21][22][23][24][25]. This protection may, however, unmask a long term oncogenic effect of the drug [26,27].…”