Streptozotocin Diabetes in Monkeys and Dogs, and Its Prevention by Nicotinamide

Schein, Philip S.; Rakieten, Nathan; Cooney, David A.; Davis, R.; Vernon, Megane

doi:10.3181/00379727-143-37355

Cited by 25 publications

(8 citation statements)

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“…The administration of 100 mg STZ/kg resulted in a diabetes-like state that was less severe than anticipated; this may result from the death of this group's markedly abnormal animals within 96 hr after STZ infusion. In general, the effects on urine output, weight gain, and kidney and liver function reported here are similar to previous findings (4,(8)(9)(10)(26)(27)(28). The fasting blood glucose levels, however, differ from those reported previously, a variance most likely due to different experimental techniques and/or variability in STZ potency (29).…”

Section: Nssupporting

confidence: 92%

Relationship between the Severity of Experimental Diabetes and Altered Lung Phospholipid Metabolism

Engle

Perelman

McMahon

et al. 1984

Experimental Biology and Medicine

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Glucose intolerance was induced in rats by iv infusion of streptozotocin (STZ) in doses of 30, 40, 50, and 100 mgjkg. Serum glucose concentrations were elevated versus controls and weight gains were reduced in a dose-dependent fashion up to 50 mgjkg. Urine outputs and blood urea nitrogen (BUN) values were higher than control values in the animals treated with 40 and 50 mg/kg and serum albumin concentrations were decreased after infusion with 50 mg STZ/kg. Lung phosphatidylcholine (PC) concentrations and dry-to-wet weight ratios were unchanged by STZ treatment, while lung protein and disaturated phosphatidylcholine (DSPC) concentrations were depressed in the 50-mg/kg group. Animals surviving treatment with lo0 mg/kg demonstrated increased fasting blood glucose levels, BUN values, and 48-hr urine outputs, and decreased lung protein levels. However, these alterations were less than those found in the 50-mg/kg animals. Pulmonary concentrations of PC, DSPC, and lung dry-to-wet weight ratios were unchanged. It was found advantageous to express the results relative to fasting blood glucose levels. This demonstrated that urine output and BUN values increased and weight gain decreased with rising glucose concentrations, but serum albumin decreased only in moderate and severe hyperglycemia. Fasting glucose concentrations greater than 400 mddl were associated with reduced lung DSPC and protein levels, while pulmonary PC and dry-to-wet weight ratios demonstrated no change with increasing hyperglycemia. 1

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Section: Nssupporting

confidence: 92%

Relationship between the Severity of Experimental Diabetes and Altered Lung Phospholipid Metabolism

Engle

Perelman

McMahon

et al. 1984

Experimental Biology and Medicine

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“…The STZ-induced changes in P450III-related activity and apoprotein levels were successfully antagonized by daily insulin therapy, demonstrating that the observed changes can be ascribed to the diabetic state rather than to STZ treatment per se. Moreover, rats which received, in addition to STZ, nicotinamide, which prevents the cytotoxic action of the diabetogen and the onset of diabetes (Schein et al, 1967), did not show any significant change from controls in P450111 activity or apoprotein levels.…”

Section: Discussionmentioning

confidence: 84%

Induction of cytochrome P450III and P450IV family proteins in streptozotocin-induced diabetes

Barnett

Gibson

Wolf³

et al. 1990

Biochemical Journal

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The effect of insulin-dependent diabetes on the hepatic microsomal activity of cytochrome P450III and P450IV family proteins was investigated in rats pretreated with streptozotocin. In order to discern between the effects of the diabetogen per se and those of the ensuing diabetes, streptozotocin-treated rats received in addition either nicotinamide to prevent the onset of diabetes or daily treatment with insulin to antagonize the effects of diabetes. Streptozotocin-treated rats displayed higher ethylmorphine and erythromycin N-demethylase activities and lauric acid hydroxylase activity. Increases were also detected immunologically by using monospecific polyclonal antibodies against the P450III and P450IV families. All effects were prevented by nicotinamide and effectively antagonized by insulin. In order to evaluate the role of the ketone bodies in the diabetes-induced increases in the above activities, rats were rendered hyperketonaemic by dietary administration of medium-chain triacylglycerols. These hyperketonaemic animals displayed high laurate hydroxylase activity and P450IV apoprotein levels, similar to those seen in the diabetic animals. Hyperketonaemia induced by dietary means caused a modest increase in the demethylation of erythromycin and had no significant effect on the N-demethylation of ethylmorphine. Furthermore, no marked increases were evident in the P450III apoprotein levels in the hyperketonaemic animals. It is concluded that insulin-dependent diabetes induces proteins of the P450III and P450IV families, and that the hyperketonaemia that accompanies diabetes is largely responsible for the changes in the latter family.

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“…specific toxic effect on i s l e t beta c e l l s . showed the drug t o be a potent diabetogenic agent in rodents, dogs and monkeys ( 2 ) . In c l i n i c a l t r i a l s , nephrotoxicity i s the major doselimiting side effect ( 3 , 4 ) .…”

mentioning

confidence: 99%

Toxicologic Evaluation of Streptozotocin (NSC 85998) in Mice, Dogs and Monkeys

Levine

Henry

Port

et al. 1980

Drug and Chemical Toxicology

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Single intravenous doses of CDF1 mice, and single and five daily intravenous treatment schedules in beagle dogs and rhesus monkeys were used to evaluate the toxicity of Streptozotocin (SZN). The major target organs in the three species were liver, kidney, lymphoid tissue and pancreatic islet beta cells. Moderate bone marrow depression and gastrointestinal toxicity were observed in the large animal species after lethal doses. Monkeys were less sensitive than the dog to the hepatotoxic effects of SZN and clinical signs of liver dysfunction were more severe in dogs after multiple doses. Microscopic lesions in the renal proximal convoluted tubules were present in the three species; these lesions appeared to be irreversible for dogs. The toxic effect on the endocrine pancreas was manifest by hyperglycemia, glucosuria, islet atrophy and beta cell degranulation. Multiple dose regimens were less toxic than single doses in dogs and monkeys in terms of the total dose received.

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Streptozotocin Diabetes in Monkeys and Dogs, and Its Prevention by Nicotinamide

Cited by 25 publications

References 1 publication

Relationship between the Severity of Experimental Diabetes and Altered Lung Phospholipid Metabolism

Relationship between the Severity of Experimental Diabetes and Altered Lung Phospholipid Metabolism

Induction of cytochrome P450III and P450IV family proteins in streptozotocin-induced diabetes

Toxicologic Evaluation of Streptozotocin (NSC 85998) in Mice, Dogs and Monkeys

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