Cancer Chemotherapy and Pharmacology

, Volume 8, Issue 1, pp 67–71 | Cite as

Alterations in hepatic and renal levels of glutathione and activities of glutathione S-transferases from rats treated with cis-dichlorodiamminelatinum-II

  • Charles L. Litterst
  • Samuel Tong
  • Yoichiro Hirokata
  • Zahid H. Siddik
Original Articles Platinum cis-Dichlorodiammineplatinum-II
Received:
Accepted:

Summary

Adult female rats were treated intraperitoneally with 8 mg/kg of cis-dichlorodiammineplatinum (II). At various times after treatment 1, 3, 5, 8, 12 days replicate animals were killed and liver and kidney cytosols examined for activity of glutathione-dependent transferase activities and levels of glutathione. Hepatic levels of glutathione were depressed by 13–28% at 1, 3, 5 days after dosing. Renal levels of glutathione were increased by 3–5 fold at 8 and 12 days after drug administration. Renal levels of glutathione were decreased at nearly all times studied with a nadir at 5 days. Activity of glutathione s-acryl transferase was increased and S-epoxidetransferase was decreased at 5, 8, 12 days after dosing. When cisplatinum was added to incubation mixtures in vitro, no changes in enzyme activities were observed. When cisplatin and reduced glutathione were determined chromatographically in tissue cytosols from treated rats, 30% of the recovered platinum was associated with glutathione. In tissue cytosols, greater than 95% of the total platinum content was retained in the supernatant when protein was precipitated with trichloroacetic acid, while only 3–5% of the protein was retained.

Keywords

Enzyme Activity Platinum Glutathione Cytosol Drug Administration 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
This is a preview of subscription content, log in to check access.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Allen RC, Gale GR, Oulla PM, Gale AO (1978) Effect of certain antitumor platinum compounds on kidney esterases. Bioinorg Chem 8: 83–89Google Scholar
  2. 2.
    Aull JL, Rice AC, Tebbetts LA (1977) Platinum complex interactions with sufhydryl groups of thymidylate synthetase. Biochemistry 16: 672–677Google Scholar
  3. 3.
    Aull JL, Allen RL, Bapat AR, Daron HH, Friedman ME, Wilson JF (1979) Effects of platinum complexes on seven enzymes. Biochim Biophys Acta 571: 352–358Google Scholar
  4. 4.
    Borsch RF, Pleasants ME (1979) Inhibition of cisplatinum nephrotoxicity by diethyldithiocarbamate. Proc Natl Acad Sci USA 76: 6611–6614Google Scholar
  5. 5.
    Burchenal JH, Kalaher K, Dew K, Lokys L, Gale G (1978) Studies of cross-resistance, synergistic combinations and blocking of activity of platinum derivatives. Biochimie 60: 961–965Google Scholar
  6. 6.
    Choie D, del Campo A, Guarino A (1980) Subcellular localization of cis-dichlorodiammineplatinum(II) in rat liver and kidney. Toxicol Appl Pharmacol 55: 245–252Google Scholar
  7. 7.
    Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82: 70–77Google Scholar
  8. 8.
    Friedman ME, Melius P, Teggins JE, McAuliffe CA (1978) Interactions of cis and trans-platinum(II) complexes with dehydrogenase enzymes in the presence of different mono-and polynucleotides: Evidence for a ternary complex. Bioinorg Chem 8: 341–353Google Scholar
  9. 9.
    Howell SB, Taetle R (1980) Effect of sodium thiosulfate on cis-dichlorodiammineplatinum(II) toxicity and antitumor activity in L1210 leukemia. Cancer Treat Rep 64: 611–616Google Scholar
  10. 10.
    Javitt NB (1976) Biochemical probes for the study of binding and conjugation of glutathione S-transferases. In: Arias I, Jakoby W (eds) Glutathione: Metabolism and function. Raven Press, New York, p 309Google Scholar
  11. 11.
    Kosower NS, Kosower EM (1976) Functional aspects of glutathione disulfide and hidden forms of glutathione. In: Arias I, Jakoby W (eds) Glutathione: Metabolism and function. Raven Press, New York, p 159Google Scholar
  12. 12.
    Kulkarni AP, Fabacher DL, Hodgson E (1980) Pesticides as inducers of hepatic drug metabolizing enzymes. II. Glutathione S-transferases. Gen Pharmacol 11: 437–441Google Scholar
  13. 13.
    LeRoy A, Wehling M, Sponseller H, Litterst C, Gram T, Guarino A, Becker D (1977) Analysis of platinum in biological materials by flameless atomic absorption spectrophotometry. Biochem Med 18: 184–191Google Scholar
  14. 14.
    Levi J, Jacobs C, Kalman S, McTigue M, Weiner M (1980) Mechanism of cis-platinum nephrotoxicity. I. Effects of sulfhydryl groups in rat kidney. J Pharmacol Exp Ther 213: 545–550Google Scholar
  15. 15.
    Lippard SJ, Hoeschele JD (1979) Binding of cis- and trans-dichlorodiammineplatinum(II) to the nucleosome core. Proc Natl Acad Sci USA 76: 6091–6095Google Scholar
  16. 16.
    Litterst CL (1981) Alterations in the toxicity of cis-dichlorodiammineplatinum-II and in tissue localization of platinum as a function of NaCl concentration in the vehicle of administration. Toxicol Appl Pharmacol 61: 99–108Google Scholar
  17. 17.
    Litterst CL, Torres IJ, Guarino AM (1977) Plasma levels and organ distribution of platinum in the rat, dog and dogfish shark following single intravenous administration of cis-dichlorodiammineplatinum(II). J Clin Hematol Oncol 7: 169–179Google Scholar
  18. 18.
    Litterst CL, Sikic BI, Mimnaugh EG, Guarino AM, Gram TE (1978) In vitro drug metabolism in male and female athymic nude mice. Life Sci 22: 1723–1730Google Scholar
  19. 19.
    Litterst CL, LeRoy AF, Guarino AM (1979) Disposition and distribution of platinum following parenteral administration of cis-dichlorodiammineplatinum(II) to animals. Cancer Treat Rep 63: 1485–1492Google Scholar
  20. 20.
    Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193: 265–275Google Scholar
  21. 21.
    Macquet JP, Butour JL (1978) Modification of DNA secondary structure upon platinum binding: a proposed model. Biochimie 60: 901–914Google Scholar
  22. 22.
    McIntyre TM, Curthoys NP (1980) The interorgan metabolism of glutathione. Int J Biochem 12: 545–551Google Scholar
  23. 23.
    Melius P, Friedman ME (1977) Complexes of platinum with polypeptides and proteins. Inorganic Perspectives in Biology and Medicine 1: 1Google Scholar
  24. 24.
    Mitchell JR, Hinson JA, Nelson SD (1976) Glutathione and drug-induced tissue lesions. In: Arias I, Jakoby W (eds) Glutathione: Metabolism and function. Raven Press, New York, p 357Google Scholar
  25. 25.
    Mize CE, Langdon RG (1962) Hepatic glutathione reductase. I. Purification and general kinetic properties. J Biol Chem 237: 1589–1595Google Scholar
  26. 26.
    Sasame HA, Boyd MR (1978) Paradoxical effects of cobaltous chloride and salts of other divalent metals on tissue levels of induced glutathione and microsomal mixed function oxidase components. J Pharmacol Exp Ther 205: 718–724Google Scholar
  27. 27.
    Siddik ZH, Drew R, Gram T (1980a) Metabolism and biliary excretion of sulfobromophthalein in vitamin A deficiency. Biochem Pharmacol 29: 2583–2588Google Scholar
  28. 28.
    Siddik ZH, Mimnaugh E, Trush M, Gram T (1980b) Effect of vitamin A deficiency on hepatic renal and pulmonary glutathione S-transferase activities in the rat. Biochem J 188: 889–893Google Scholar
  29. 29.
    Strothcamp KG, Lippard SJ (1976) Platinum binds selectively to phosphorothioate groups in mono- and polynucleotides: A general method for heavy metal staining of specific nucleotides. Proc Natl Acad Sci USA 73: 2536–2540Google Scholar
  30. 30.
    Tietze F (1969) Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathion: Applications to mammalian blood and other tissues. Anal Biochem 27: 502–522Google Scholar
  31. 31.
    Ward J, Fauvie K (1976) Nephrotoxic effects of cis-diamminedichloroplatinum(II) in male F344 rats. Toxicol Appl Pharmacol 38: 535–547Google Scholar
  32. 32.
    Whikehart DR (1975) Total and oxidized glutathione in bovine corneal epithelium and endothelium. Exp Eye Res 21: 89–92Google Scholar
  33. 33.
    Yuhas JM, Culo F (1980) Selective inhibition of the nephrotoxicity of cis-dichlorodiammineplatinum(II) by WR-2721 without altering its antitumor properties. Cancer Treat Rep 64: 57–64Google Scholar

Copyright information

© Springer-Verlag 1982

Authors and Affiliations

  • Charles L. Litterst
    • 1
  • Samuel Tong
    • 1
  • Yoichiro Hirokata
    • 1
  • Zahid H. Siddik
    • 1
  1. 1.Laboratory of Medicinal Chemistry and Biology, Division of Cancer Treatment, National Cancer InstituteNational Institutes of HealthBethesdaUSA

Personalised recommendations