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. 1986 Aug 1;237(3):713–721. doi: 10.1042/bj2370713

Differential effect of cis-platinum (cis-diamminedichloroplatinum) on regulation of liver and kidney haem and haemoprotein metabolism. Possible involvement of gamma-glutamyl-cycle enzymes.

M D Maines
PMCID: PMC1147049  PMID: 2879531

Abstract

The treatment of rats with cis-platinum (cis-diamminedichloroplatinum) for 1, 3 or 7 days elicited vastly different responses in the liver and the kidney in activities of enzymes of haem-metabolism pathway and gamma-glutamyl-cycle enzymes. The differences resided in the magnitude, direction and the time course of responses. In general, the liver was by far less severely affected, and when a response was elicited, it displayed an earlier onset (1-3 days), with a return to normal at 7 days. In the kidney, however, the effects were notable after 3 days of treatment, and became more pronounced at 7 days. Specifically, the activity of 5-aminolaevulinic acid (ALA) synthetase and contents of cytochrome P-450 and the microsomal haem were decreased in the liver. In contrast, in the kidney, cytochrome P-450 and haem concentrations were significantly increased, with no change in ALA synthetase activity. The increase in the kidney haem content appeared to reflect an increased formation of haem, as suggested by the elevated activity of ferrochelatase and the concomitant decrease in tissue porphyrin levels. In the kidney, a time-dependent and pronounced inhibition of activities of gamma-glutamylcysteine synthetase, the rate-limiting enzyme in glutathione production, and gamma-glutamyl transpeptidase, the first enzyme in glutathione breakdown, were observed. The enzyme activities, 7 days after treatment, were only 40 and 60% of the control values respectively. In contrast, these enzyme activities were not affected in the liver. Complexing cis-platinum with cysteine considerably intensified the entire spectrum of effects of cis-platinum in the kidney. Notably, cytochrome P-450 concentration and haem oxygenase activity were increased to about 3.5 and 6 times the control values, respectively. gamma-Glutamylcysteine synthetase activity was decreased to less than 20% of the control. It is suggested that the differential effectiveness of cis-platinum in the liver and the kidney in alternating haem metabolism is related to the vast differences which exist between these organs in the activities of gamma-glutamyl-cycle enzymes. It is further suggested that this may promote the formation in the kidney, but not in the liver, of a cis-platinum-cysteine complex that is more stable, and thus biologically more effective, than the parent compound.

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Selected References

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  1. Blachley J. D., Hill J. B. Renal and electrolyte disturbances associated with cisplatin. Ann Intern Med. 1981 Nov;95(5):628–632. doi: 10.7326/0003-4819-95-5-628. [DOI] [PubMed] [Google Scholar]
  2. Borch R. F., Pleasants M. E. Inhibition of cis-platinum nephrotoxicity by diethyldithiocarbamate rescue in a rat model. Proc Natl Acad Sci U S A. 1979 Dec;76(12):6611–6614. doi: 10.1073/pnas.76.12.6611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Boyland E., Chasseaud L. F. The effect of some carbonyl compounds on rat liver glutathione levels. Biochem Pharmacol. 1970 Apr;19(4):1526–1528. doi: 10.1016/0006-2952(70)90075-4. [DOI] [PubMed] [Google Scholar]
  4. Cohn V. H., Lyle J. A fluorometric assay for glutathione. Anal Biochem. 1966 Mar;14(3):434–440. doi: 10.1016/0003-2697(66)90286-7. [DOI] [PubMed] [Google Scholar]
  5. Daley-Yates P. T., McBrien D. C. The inhibition of renal ATPase by cisplatin and some biotransformation products. Chem Biol Interact. 1982 Jul 1;40(3):325–334. doi: 10.1016/0009-2797(82)90155-7. [DOI] [PubMed] [Google Scholar]
  6. GRANICK S., URATA G. Increase in activity of alpha-aminolevulinic acid synthetase in liver mitochondria induced by feeding of 3,5-dicarbethoxy-1,4-dihydrocollidine. J Biol Chem. 1963 Feb;238:821–827. [PubMed] [Google Scholar]
  7. Granick S., Sinclair P., Sassa S., Grieninger G. Effects by heme, insulin, and serum albumin on heme and protein synthesis in chick embryo liver cells cultured in a chemically defined medium, and a spectrofluorometric assay for porphyrin composition. J Biol Chem. 1975 Dec 25;250(24):9215–9225. [PubMed] [Google Scholar]
  8. Jollie D. R., Maines M. D. Effect of cis-platinum on kidney cytochrome P-450 and heme metabolism: evidence for the regulatory role of the pituitary hormones. Arch Biochem Biophys. 1985 Jul;240(1):51–59. doi: 10.1016/0003-9861(85)90007-4. [DOI] [PubMed] [Google Scholar]
  9. Jones M. S., Jones O. T. Ferrochelatase of Rhodopseudomonas spheroides. Biochem J. 1970 Sep;119(3):453–462. doi: 10.1042/bj1190453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kutty R. K., Maines M. D. Oxidation of heme c derivatives by purified heme oxygenase. Evidence for the presence of one molecular species of heme oxygenase in the rat liver. J Biol Chem. 1982 Sep 10;257(17):9944–9952. [PubMed] [Google Scholar]
  11. Kutty R. K., Maines M. D. Purification and characterization of biliverdin reductase from rat liver. J Biol Chem. 1981 Apr 25;256(8):3956–3962. [PubMed] [Google Scholar]
  12. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  13. Leyland-Jones B., Morrow C., Tate S., Urmacher C., Gordon C., Young C. W. Cis-diamminedichloroplatinum(II) nephrotoxicity and its relationship to renal gamma-glutamyl transpeptidase and glutathione. Cancer Res. 1983 Dec;43(12 Pt 1):6072–6076. [PubMed] [Google Scholar]
  14. Litterst C. L., LeRoy A. F., Guarino A. M. Disposition and distribution of platinum following parenteral administration of cis-dichlorodiammineplatinum(II) to animals. Cancer Treat Rep. 1979 Sep-Oct;63(9-10):1485–1492. [PubMed] [Google Scholar]
  15. Litterst C. L., Mimnaugh E. G., Reagan R. L., Gram T. E. Comparison of in vitro drug metabolism by lung, liver, and kidney of several common laboratory species. Drug Metab Dispos. 1975 Jul-Aug;3(4):259–265. [PubMed] [Google Scholar]
  16. Litterst C. L., Tong S., Hirokata Y., Siddik Z. H. Stimulation of microsomal drug oxidation in liver and kidney of rats treated with the oncolytic agent cis-dichlorodiammineplatinum-II. Pharmacology. 1983;26(1):46–53. doi: 10.1159/000137768. [DOI] [PubMed] [Google Scholar]
  17. MAUZERALL D., GRANICK S. The occurrence and determination of delta-amino-levulinic acid and porphobilinogen in urine. J Biol Chem. 1956 Mar;219(1):435–446. [PubMed] [Google Scholar]
  18. Maines M. D. Enhancement and inhibition of enzymes of heme metabolism by diethyl maleate in the rat kidney. Arch Biochem Biophys. 1982 Jun;216(1):17–26. doi: 10.1016/0003-9861(82)90183-7. [DOI] [PubMed] [Google Scholar]
  19. Maines M. D., Kappas A. Cobalt induction of hepatic heme oxygenase; with evidence that cytochrome P-450 is not essential for this enzyme activity. Proc Natl Acad Sci U S A. 1974 Nov;71(11):4293–4297. doi: 10.1073/pnas.71.11.4293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Maines M. D., Kappas A. Cobalt stimulation of heme degradation in the liver. Dissociation of microsomal oxidation of heme from cytochrome P-450. J Biol Chem. 1975 Jun 10;250(11):4171–4177. [PubMed] [Google Scholar]
  21. Maines M. D., Kappas A. Metals as regulators of heme metabolism. Science. 1977 Dec 23;198(4323):1215–1221. doi: 10.1126/science.337492. [DOI] [PubMed] [Google Scholar]
  22. Maines M. D., Kappas A. Regulation of heme pathway enzymes and cellular glutathione content by metals that do not chelate with tetrapyrroles: blockade of metal effects by thiols. Proc Natl Acad Sci U S A. 1977 May;74(5):1875–1878. doi: 10.1073/pnas.74.5.1875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Maines M. D. New developments in the regulation of heme metabolism and their implications. Crit Rev Toxicol. 1984;12(3):241–314. doi: 10.3109/10408448409021604. [DOI] [PubMed] [Google Scholar]
  24. Maines M. D. Regional distribution of the enzymes of haem biosynthesis and the inhibition of 5-aminolaevulinate synthase by manganese in the rat brain. Biochem J. 1980 Aug 15;190(2):315–321. doi: 10.1042/bj1900315. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Marver H. S., Collins A., Tschudy D. P., Rechcigl M., Jr Delta-aminolevulinic acid synthetase. II. Induction in rat liver. J Biol Chem. 1966 Oct 10;241(19):4323–4329. [PubMed] [Google Scholar]
  26. Massey V., Williams C. H., Jr On the reaction mechanism of yeast glutathione reductase. J Biol Chem. 1965 Nov;240(11):4470–4480. [PubMed] [Google Scholar]
  27. Meister A., Griffith O. W., Novogrodsky A., Tate S. S. New aspects of glutathione metabolism and translocation in mammals. Ciba Found Symp. 1979;(72):135–161. doi: 10.1002/9780470720554.ch9. [DOI] [PubMed] [Google Scholar]
  28. Meister A. New aspects of glutathione biochemistry and transport: selective alteration of glutathione metabolism. Fed Proc. 1984 Dec;43(15):3031–3042. [PubMed] [Google Scholar]
  29. Meister A. On the cycles of glutathione metabolism and transport. Curr Top Cell Regul. 1981;18:21–58. doi: 10.1016/b978-0-12-152818-8.50009-8. [DOI] [PubMed] [Google Scholar]
  30. OMURA T., SATO R. THE CARBON MONOXIDE-BINDING PIGMENT OF LIVER MICROSOMES. II. SOLUBILIZATION, PURIFICATION, AND PROPERTIES. J Biol Chem. 1964 Jul;239:2379–2385. [PubMed] [Google Scholar]
  31. Peck H. D., Jr, Tedro S., Kamen M. D. Sulfite reductase activity in extracts of various photosynthetic bacteria. Proc Natl Acad Sci U S A. 1974 Jun;71(6):2404–2406. doi: 10.1073/pnas.71.6.2404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Rosenberg B., VanCamp L., Trosko J. E., Mansour V. H. Platinum compounds: a new class of potent antitumour agents. Nature. 1969 Apr 26;222(5191):385–386. doi: 10.1038/222385a0. [DOI] [PubMed] [Google Scholar]
  33. Sekura R., Meister A. Covalent interaction of L-2-amino-4-oxo-5-chloropentanoate at glutamate binding site of gamma-glutamylcysteine synthetase. J Biol Chem. 1977 Apr 25;252(8):2606–2610. [PubMed] [Google Scholar]
  34. TAUSSKY H. H., SHORR E. A microcolorimetric method for the determination of inorganic phosphorus. J Biol Chem. 1953 Jun;202(2):675–685. [PubMed] [Google Scholar]
  35. Tate S. S., Meister A. Interaction of gamma-glutamyl transpeptidase with amino acids, dipeptides, and derivatives and analogs of glutathione. J Biol Chem. 1974 Dec 10;249(23):7593–7602. [PubMed] [Google Scholar]
  36. Tenhunen R., Marver H. S., Schmid R. The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Natl Acad Sci U S A. 1968 Oct;61(2):748–755. doi: 10.1073/pnas.61.2.748. [DOI] [PMC free article] [PubMed] [Google Scholar]

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