Skip to main content
SpringerLink
Log in

Mechanism of induction of heme oxygenase by metalloporphyrins in primary chick embryo liver cells: Evidence against a stress-mediated response

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Heme oxygenase catalyzes the first and rate-controlling step in heme catabolism. One of the two forms of heme oxygenase (heme oxygenase-1) has been shown to be increased by heme, metals, and in some systems, by certain environmental stresses. However, it remains uncertain whether heme induces hepatic heme oxygenase-1 by a general stress response, or a specific heme-dependent cellular response. The work communicated here explores this issue by examining possible mechanisms whereby heme and other metalloporphyrins induce heme oxygenase-1 in normal liver cells. Primary cultures of chick embryo liver cells were tested for their ability to increase heme oxygenase mRNA after exposure to selected metalloporphyrins (heme, chromium mesoporphyrin, cobalt protoporphyrin and manganese protoporphyrin). The ability of antioxidants to decrease metalloporphyrin-mediated induction of heme oxygenase-1 mRNA was also tested. Our results indicate that: 1) the increase in heme oxygenase-1 mRNA mediated by heme or other metalloporphyrins may involve a short-lived protein(s) since the increase was prevented by several inhibitors of protein synthesis; and 2) in normal liver cells, heme-dependent oxidative stress does not play a key role in the heme-mediated induction of heme oxygenase-1. We conclude that heme and other non-heme metalloporphyrins induce heme oxygenase-1 through a mechanism requiring protein synthesis, not because metalloporphyrins increase cellular oxidative or other stress.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Kikuchi G, Yoshida T: Function and induction of the microsomal heme oxygenase. Mol Cell Biol 53/54: 163–183, 1983

    Google Scholar 

  2. Rotenberg MO, Maines MD: Isolation, characterization, and expression in Escherichia coli of a cDNA encoding rat heme oxygenase-2. J Biol Chem 265: 7501–7506, 1990

    PubMed  Google Scholar 

  3. Bonkovsky HL, Healey JF, Pohl J: Purification and characterization of heme oxygenase from chick liver – Comparison of the avian and mammalian enzymes. Eur J Biochem 189: 155–166, 1990

    PubMed  Google Scholar 

  4. Rodgers PA, Stevenson DK: Developmental biology of heme oxygenase. Clin Perinatol 17: 275–291, 1990

    PubMed  Google Scholar 

  5. Maines MD: Heme oxygenase: function, multiplicity, regulatory mechanisms, and clinical applications. FASEB J 2: 2557–2568, 1988

    PubMed  Google Scholar 

  6. Chowdhury JR, Wolkoff AW, Arias IM: Hereditary jaundice and disorders of bilirubin metabolism. In: The Metabolic Basis of Inherited Disease 6th Ed. CR Scriver, AL Beaudet, WS Sly, D Valle (eds). McGraw-Hill, Inc., New York, NY, 1989, pp 1367–1408

    Google Scholar 

  7. Lincoln BC, Aw TY, Bonkovsky HL: Heme catabolism in cultured hepatocytes: evidence that heme oxygenase is the predominant path-way and that a proportion of synthesized heme is converted rapidly to biliverdin. Biochim Biophys Acta 992: 49–58, 1989

    PubMed  Google Scholar 

  8. Srivastava KK, Cable EE, Donohue SE, Bonkovsky HL: Molecular basis for heme-dependent induction of heme oxygenase in primary cultures of chick embryo hepatocytes. Demonstration of acquired refractoriness to heme. Eur J Biochem 213: 909–917, 1993

    PubMed  Google Scholar 

  9. Lincoln BC, Healey JF, Bonkovsky HL: Regulation of hepatic haem metabolism. Disparate mechanisms of induction of haem oxygenase by drugs and metals, Biochem J 250: 189–196, 1988

    PubMed  Google Scholar 

  10. Tomaro ML, Frydman J, Frydman RB: Heme oxygenase induction by CoCl2, Co-protoporphyrin IX, phenylhydrazine, and diamide: Evidence for oxidative stress involvement. Arch Biochem Biophys 286: 610–617, 1991

    PubMed  Google Scholar 

  11. Smith TJ, Haque S, Drummond GS: Induction of heme oxygenase mRNA by cobalt protoporphyrin in rat liver, Biochim. Biophys Acta 1073: 221–224, 1991

    Google Scholar 

  12. Cable EE, Pepe JA, Karamitsios NC, Lambrecht RW, Bonkovsky HL: Differential effects of metalloporphyrins on mRNA levels of Damino-levulinate synthase and heme oxygenase: studies in cultured chick embryo liver cells. J Clin Invest 94: 649–654, 1994

    PubMed  Google Scholar 

  13. Sardana MK, Sassa S, Kappas A: Metal ion-mediated regulation of heme oxygenase induction in cultured avian liver cells. J Biol Chem 257: 4806–4811, 1982

    PubMed  Google Scholar 

  14. Basu-Modak S, Tyrrell RM: Singlet oxygen: A primary effector in the ultraviolet A/near-visible light induction of the human heme oxygenase gene. Cancer Res 53: 4505–4510, 1993

    PubMed  Google Scholar 

  15. Lutton JD, da Silva JL, Moqattash S, Brown AC, Levere RD, Abraham NG: Differential induction of heme oxygenase in the hepatocarcinoma cell line (Hep3B) by environmental agents. J Cell Biochem 49: 259–265, 1992

    PubMed  Google Scholar 

  16. Applegate LA, Luscher P, Tyrrell RM: Induction of heme oxygenase: A general response to oxidant stress in cultured mammalian cells. Cancer Res 51: 974–978, 1991

    PubMed  Google Scholar 

  17. Keyse SM, Applegate LA, Tromvoukis Y, Tyrrell RM: Induction of the heme oxygenase gene in human skin fibroblasts by hydrogen peroxide and UVA (365 nm) radiation: evidence for the involvment of the hydroxyl radical. Mol Cell Biol 10: 4967–4969, 1990

    PubMed  Google Scholar 

  18. Nath KA: The functional significance of induction of heme oxygenase by oxidant stress. J Lab Clin Med 123: 461–463, 1994

    PubMed  Google Scholar 

  19. Nutter LM, Sierra EE, Ngo EO: Heme oxygenase does not protect human cells against oxidant stress. J Lab Clin Med 123: 506–514

  20. Tyrrell RM, Basumodak S: Transient enhancement of heme oxygenase 1 mRNA accumulation: a marker of oxidative stress to eukaryotic cells. Methods Enzymol 234: 224–235, 1994

    PubMed  Google Scholar 

  21. Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN: Bi-lirubin is an antioxidant of possible physiologic importance. Science 235: 1043–1047, 1987

    PubMed  Google Scholar 

  22. Balla G, Vercellotti GM, Muller-Eberhard U, Eaton J, Jacob HS: Exposure of endothelial cells to free heme potentiates damage mediated by granulocytes and toxic oxygen species. Lab Invest 64: 648–655, 1991

    PubMed  Google Scholar 

  23. Mitani K, Fujita H, Kappas A, Sassa S: Heme oxygenase is a positive acute-phase reactant in human Hep3B hepatoma cells. Blood 79: 1255–1259, 1992

    PubMed  Google Scholar 

  24. Mitani K, Fujita H, Sassa S, Kappas A: Activation of heme oxygenase and heat shock protein 70 genes by stress in human hepatoma cells. Biochem Biophys Res Commun 166: 1429–1434, 1990

    PubMed  Google Scholar 

  25. Ewing JF, Haber SN, Maines MD: Normal and heat-induced patterns of expression of heme oxygenase-1 (HSP32) in rat brain: hyperther mia causes rapid induction of mRNA and protein. Journal of Neurochemistry 58: 1140–1149, 1992

    PubMed  Google Scholar 

  26. Landaw SA, Drummond GS, Kappas A: Targeting of heme oxygenase inhibitors to the spleen markedly increases their ability to diminish bilirubin production. Pediatrics 84: 1091–1096, 1989

    PubMed  Google Scholar 

  27. Greene YJ, Healey JF, Bonkovsky HL: Immunochemical studies of. haem oxygenase. Preparation and characterization of antibodies to chick liver haem oxygenase and their use in detecting and quantifying amounts of haem oxygenase protein. Biochem J 279: 849–854, 1991

    PubMed  Google Scholar 

  28. Nascimento AL, Luscher P, Tyrrell RM: Ultraviolet A (320–380 nm) radiation causes an alteration in the binding of a specific protein/protein complex to a short region of the promoter of the human heme oxygenase 1 gene. Nucl Acids Res 21: 1103–1109, 1993

    PubMed  Google Scholar 

  29. Keyse SM, Tyrrell RM: Heme oxygenase is the major 32-kDA stress protein induced in human skin fibroblasts by UVA radiation, hydrogen peroxide, and sodium arsenite. Proc Natl Acad Sci 86: 99–103, 1989

    PubMed  Google Scholar 

  30. Maines MD, Sinclair P: Cobalt regulation of heme synthesis and degradation in avian embryo liver cell culture. J Biol Chem 252: 219–223, 1977

    PubMed  Google Scholar 

  31. Sunderman FW Jr: Metal induction of heme oxygenase. Ann N Y Acad Sci 514, 65–80, 1987

    PubMed  Google Scholar 

  32. Lin JH, Villalon P, Martasek P, Abraham NG: Regulation of heme oxygenase gene expression by cobalt in rat liver and kidney. Eur J Biochem 192: 577–582, 1990

    PubMed  Google Scholar 

  33. Yoshida T, Arakaki M, Kumakawa J, Kuroiwa Y: An induction of heme oxygenase and its possible relation to the decrease of cytochrome P-450 content during liver regeneration. J Pharmacobio-Dynamics 7: 112–119, 1984

    Google Scholar 

  34. Yoshida T, Oguro T, Numazawa S, Kuroiwa Y: Effects of phorone (diisopropylidene acetone), a glutathione (GSH) depletor, on hepatic enzymes involved in drug and heme metabolism in rats: evidence that phorone is a potent inducer of heme oxygenase. Biochem Biophys Res Commun 145: 502–508, 1987

    PubMed  Google Scholar 

  35. Mitani K, Fujita H, Sassa S, Kappas A: Heat shock induction of heme oxygenase mRNA in human Hep 3B hepatoma cells. Biochem Biophys Res Commun 165: 437–441, 1989

    PubMed  Google Scholar 

  36. Cable E, Greene Y, Healey J, Evans CO, Bonkovsky H: Mechanism of synergistic induction of hepatic heme oxygenase by glutethimide and iron: studies in cultured chick embryo liver cells. Biochem Biophys Res Commun 168: 176–181, 1990

    PubMed  Google Scholar 

  37. Cable EE, Pepe JA, Gildemeister OS, Lambrecht RW, Bonkovsky HL: Induction of heme oxygenase by metalloporphyrins in primary chick embryo liver cells: Evidence for a protein-but not a stress-dependent response. Hepatology 20: 332A, 1995

    Google Scholar 

  38. Cable EE, Cable JW, Bonkovsky HL: Repression of hepatic d-aminolevulinate synthase by heme and metalloporphyrins: relationship to inhibition of heme oxygenase. Hepatology 18: 119–127, 1993

    PubMed  Google Scholar 

  39. Cable EE, Healey JF, Greene Y, Evans CO, Bonkovsky HL: Synergistic induction of d-aminolevulinate synthase by glutethimide and iron: relationship to the synergistic induction of heme oxygenase. Biochim Biophys Acta 1080: 245–251, 1991

    PubMed  Google Scholar 

  40. Shedlofsky SI, Bonkovsky HL, Sinclair PR, Sinclair JF, Bement, WJ, Pomeroy JS: Iron loading of cultured hepatocytes: effect of iron on 5-minolevulinate synthase is independent of lipid peroxidation. Biochem J 212: 321–330, 1983

    PubMed  Google Scholar 

  41. Lambrecht RW, Cable JW, Pepe JA, Bonkovsky HL: 3,5,5'-Trimethylhexanoylferrocene induction of heme oxygenase activity in normal hepatocytes. Biochem Pharmacol 47: 1669–1676, 1994

    PubMed  Google Scholar 

  42. Hollander MC, Fornace AJ: Estimation of relative mRNA content by filter hybridization to a polythymidylate probe. Biotechniques 9: 174–179, 1990

    PubMed  Google Scholar 

  43. Sambrook J, Fritsch EF, Maniatis T: In: Molecular cloning. A labora-tory manual. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 1989

    Google Scholar 

  44. Hall ED, Braughler JM, McCall JM: Role of oxygen radicals in stroke: effects of the 21-aminosteroids (lazaroids). A novel class of antioxidants. Prog Clin Biol Res 361: 351–362, 1990

    PubMed  Google Scholar 

  45. Di Mascio P, Murphy ME, Sies H: Antioxidant defense systems: the role of carotenoids, tocopherols, and thiols. Am J Clin Nutr 53: 194S–200S, 1991

    PubMed  Google Scholar 

  46. Hartley A, Davies MJ, Rice-Evans C: Desferrioxamine and membrane oxidation: Radical scavenger or iron chelator? Biochem Soc Trans 17: 1002–1003, 1989

    PubMed  Google Scholar 

  47. Maines MD: New developments in the regulation of heme metabolism and their implications. Critical Reviews in Toxicology 12: 241–314, 1984

    PubMed  Google Scholar 

  48. Ren YF, Palmiter RD, Smith A: Role of protein kinase C and reactive oxygen intermediates in transcriptional activation of genes in response to hemopexin (HPX). FASEB J 7: 1054, 1993

    Google Scholar 

  49. Ding L, Etemad-Moghadam G, Meunier B: Oxidative cleavage of DNA mediated by hybrid metalloporphyrin-ellipticine molecules and functionalized metalloporphyrin precursors. Biochemistry 29: 7868–7875, 1990

    PubMed  Google Scholar 

  50. Sehlstedt U, Kim SK, Carter P, Goodisman J, Vollano JF, Norden B, Dabrowiak JC: Interaction of cationic porphyrins with DNA. Biochemistry 33: 417–426

  51. Derijard B, Hibi M, Wu IH, Barrett T, Su B, Deng T, Karin M, Davis RJ: JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-jun activation domain. Cell 76: 1025–1037, 1994

    PubMed  Google Scholar 

  52. Davis RJ: The mitogen-activated protein kinase signal transduction pathway. J Biol Chem 268: 14553–14556, 1993

    PubMed  Google Scholar 

  53. Stohs SJ, Bagchi D: Oxidative mechanisms in the toxicity of metal ions. Free Radical Biol Med 18: 321–336, 1995

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, USA

    Edward E. Cable, Otto S. Gildemeister, Joyce A. Pepe, Richard W. Lambrecht & Herbert L. Bonkovsky

  2. Biochemistry and Molecularbiology, USA

    Herbert L. Bonkovsky

  3. The Center of Study of Disorders of Iron and Porphyrin Metabolism, University of Massachusetts Medical Center, Worcester, MA, 01655, USA

    Edward E. Cable, Otto S. Gildemeister, Joyce A. Pepe, Richard W. Lambrecht & Herbert L. Bonkovsky

Authors
  1. Edward E. Cable
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Otto S. Gildemeister
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joyce A. Pepe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Richard W. Lambrecht
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Herbert L. Bonkovsky
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cable, E.E., Gildemeister, O.S., Pepe, J.A. et al. Mechanism of induction of heme oxygenase by metalloporphyrins in primary chick embryo liver cells: Evidence against a stress-mediated response. Mol Cell Biochem 169, 13–20 (1997). https://doi.org/10.1023/A:1006817207166

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1006817207166

Search

Navigation