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. 1974 Sep;54(3):672–677. doi: 10.1172/JCI107805

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

Tom Anderson 1,2, Philip S Schein 1,2, Mary G McMenamin 1,2, David A Cooney 1,2
PMCID: PMC301601  PMID: 4369217

Abstract

The diabetogenic activity of streptozotocin has been correlated with a reduction in pyridine nucleotide synthesis in the mouse pancreatic islet. To determine the specificity of this reduction for diabetogenicity, a comparative study of streptozotocin, its cytotoxic moiety, 1-methyl-1-nitrosourea, and alloxan was performed. Streptozotocin administered intraperitoneally (i.p.) producd a dose-related reduction in islet NAD which was proportional to the degree of diabetogenicity. A diabetogenic dose, 200 mg/kg, attained a peak plasma N-nitroso intact streptozotocin concentration of 0.224 μmol/ml and reduced the mean islet NAD from a control of 0.78 to 0.15 pmol. At borderline, 150 mg/kg, and nondiabetogenic, 100 mg/kg, doses, plasma concentrations reached 0.161 and 0.136 μmol/ml, and NAD was 0.36 and 0.86 pmol/islet, respectively. 1-Methyl-1-nitrosourea, 100 mg/kg, attained a maximum N-nitroso intact 1-methyl-1-nitrosourea concentration of 0.162 μmol/ml and reduced the mean NAD to 0.58 pmol/islet, and was nondiabetogenic; 200 mg/kg attained a peak plasma concentration of 0.344 μmol/ml and depressed NAD to 0.38 pmol/islet, and was inconsistently diabetogenic. Islet NAD of 0.4 pmol/islet or greater is required for integrity of the beta cell. A diabetogenic dose of alloxan, 500 mg/kg, did not depress NAD, 0.85 pmol/islet, therefore confirming that its mechanism of diabetogenicity differs from that of streptozotocin.

In vivo uptake of [methyl-14C]streptozotocin by islets was 3.8 times that of [methyl-14C]-1-methyl-1-nitrosourea, whereas uptake by the exocrine pancreas favored 1-methyl-1-nitrosourea over streptozotocin 2.4:1. The decreased islet uptake of 1-methyl-1-nitrosourea correlates with the 3.5 times increased molar dosage required to produce islet NAD depression comparable to that of streptozotocin, 150 mg/kg. These studies indicate that the glucose carrier of streptozotocin facilitates uptake of its cytotoxic group, 1-methyl-1-nitrosourea, into islets.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. BURTON K. A study of the conditions and mechanism of the diphenylamine reaction for the colorimetric estimation of deoxyribonucleic acid. Biochem J. 1956 Feb;62(2):315–323. doi: 10.1042/bj0620315. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Dulin W. E., Wyse B. M. Studies on the ability of compounds to block the diabetogenic activity of streptozotocin. Diabetes. 1969 Jul;18(7):459–466. doi: 10.2337/diab.18.7.459. [DOI] [PubMed] [Google Scholar]
  3. Herr R. R., Jahnke J. K., Argoudelis A. D. The structure of streptozotocin. J Am Chem Soc. 1967 Aug 30;89(18):4808–4809. doi: 10.1021/ja00994a053. [DOI] [PubMed] [Google Scholar]
  4. Junod A., Lambert A. E., Orci L., Pictet R., Gonet A. E., Renold A. E. Studies of the diabetogenic action of streptozotocin. Proc Soc Exp Biol Med. 1967 Oct;126(1):201–205. doi: 10.3181/00379727-126-32401. [DOI] [PubMed] [Google Scholar]
  5. KAPLAN N. O., GOLDIN A., HUMPHREYS S. R., CIOTTI M. M., STOLZENBACH F. E. Pyridine nucleotide synthesis in the mouse. J Biol Chem. 1956 Mar;219(1):287–298. [PubMed] [Google Scholar]
  6. KINGSLEY G. R., GETCHELL G. Direct ultramicro glucose oxidase method for determination of glucose in biologic fluids. Clin Chem. 1960 Oct;6:466–475. [PubMed] [Google Scholar]
  7. LAZAROW A., LIAMBIES J., TAUSCH A. J. Protection against diabetes with nicotinamide. J Lab Clin Med. 1950 Aug;36(2):249–258. [PubMed] [Google Scholar]
  8. Lazarus S. S., Shapiro S. H. Influence of nicotinamide and pyridine nucleotides on streptozotocin and alloxan-induced pancreatic B cell cytotoxicity. Diabetes. 1973 Jul;22(7):499–506. doi: 10.2337/diab.22.7.499. [DOI] [PubMed] [Google Scholar]
  9. SCHABEL F. M., Jr, JOHNSTON T. P., McCALEB G. S., MONTGOMERY J. A., LASTER W. R., SKIPPER H. E. Experimental evaluation of potential anticancer agents VIII. Effects of certain nitrosoureas on intracerebral L1210 leukemia. Cancer Res. 1963 Jun;23:725–733. [PubMed] [Google Scholar]
  10. SOKOLSKI W. T., VAVRA J. J., HANKA L. J. Assay methods and antibacterial studies on streptozotocin. Antibiot Annu. 1959;7:241–246. [PubMed] [Google Scholar]
  11. Schein P. S. 1-methyl-1-nitrosourea and dialkylnitrosamine depression of nicotinamide adenine dinucleotide. Cancer Res. 1969 Jun;29(6):1226–1232. [PubMed] [Google Scholar]
  12. Schein P. S., Cooney D. A., McMenamin M. G., Anderson T. Streptozotocin diabetes--further studies on the mechanism of depression of nicotinamide adenine dinucleotide concentrations in mouse pancreatic islets and liver. Biochem Pharmacol. 1973 Oct 15;22(20):2625–2631. doi: 10.1016/0006-2952(73)90071-3. [DOI] [PubMed] [Google Scholar]
  13. Schein P. S., Cooney D. A., Vernon M. L. The use of nicotinamide to modify the toxicity of streptozotocin diabetes without loss of antitumor activity. Cancer Res. 1967 Dec;27(12):2324–2332. [PubMed] [Google Scholar]
  14. Schein P. S. Islet cell tumors: current concepts and management. Ann Intern Med. 1973 Aug;79(2):239–257. doi: 10.7326/0003-4819-79-2-239. [DOI] [PubMed] [Google Scholar]
  15. Schein P. S., Loftus S. Streptozotocin: depression of mouse liver pyridine nucleotides. Cancer Res. 1968 Aug;28(8):1501–1506. [PubMed] [Google Scholar]
  16. Schein P., Kahn R., Gorden P., Wells S., Devita V. T. Streptozotocin for malignant insulinomas and carcinoid tumor. Report of eight cases and review of the literature. Arch Intern Med. 1973 Oct;132(4):555–561. [PubMed] [Google Scholar]
  17. Stauffacher W., Burr I., Gutzeit A., Beaven D., Veleminsky J., Renold A. E. Streptozotocin diabetes: time course of irreversible B-cell damage; further observations on prevention by nicotinamide. Proc Soc Exp Biol Med. 1970 Jan;133(1):194–200. doi: 10.3181/00379727-133-34439. [DOI] [PubMed] [Google Scholar]
  18. WATKINS D., COOPERSTEIN S. J., LAZAROW A. EFFECT OF ALLOXAN ON PERMEABILITY OF PANCREATIC ISLET TISSUE IN VITRO. Am J Physiol. 1964 Aug;207:436–440. doi: 10.1152/ajplegacy.1964.207.2.436. [DOI] [PubMed] [Google Scholar]
  19. Watkins D., Cooperstein S. J., Lazarow A. Effect of sulfhydryl reagents on permeability of toadfish islet tissue. Am J Physiol. 1970 Aug;219(2):503–509. doi: 10.1152/ajplegacy.1970.219.2.503. [DOI] [PubMed] [Google Scholar]
  20. ZIMMER F. E. ISLET-CELL CARCINOMA TREATED WITH ALLOXAN; ASSOCIATED WITH CALCIFIED HEPATIC METASTASES AND THYROTOXIC MYOPATHY. Ann Intern Med. 1964 Sep;61:543–549. doi: 10.7326/0003-4819-61-3-543. [DOI] [PubMed] [Google Scholar]

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