Advertisement

Regulation of Heme Biosynthesis in Chick Embryo Liver Cells

  • G. S. Marks
  • J. E. Mackie
  • S. A. McCluskey
  • D. S. Riddick
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 271)

Abstract

According to current evidence heme controls the heme biosynthetic pathway primarily by controlling translocation of inactive pre-ALA-S from the cytosol into the mitochondrion, where ALA-S is active. A secondary mechanism involves inhibition by heme of transcription of the ALA-S gene. Porphyrinogenic drugs act by lowering a regulatory “free heme pool” by three different mechanisms: (a) by mechanism-based inactivation of cytochrome P-450 resulting in N-alkylprotoporphyrin formation and ferrochelatase inhibition, (b) by mechanism-based inactivation of cytochrome P-450 resulting in continuous heme destruction, (c) by enhanced generation of active oxygen species which interact with an endogenous substrate to form an inhibitor of uroporphyrinogen decarboxylase. It is also possible that porphyrinogenic drugs may exert a direct effect on the nucleus to increase formation of ALA-S mRNA.

The rate-controlling enzyme of the heme biosynthetic pathway is δ-aminolevulinic acid synthase (ALA-S). This enzyme which is located in the mitochondrion catalyzes the condensation of succinyl-CoA and glycine to form δ-aminolevulinic acid (ALA). ALA passes out of the mitochondria into the cytoplasm where two molecules condense together to form the pyrrole, porphobilinogen (PBG). The enzyme involved in catalyzing this reaction is δ-aminolevulinic acid dehydratase (ALA-D). PBG is converted to a linear tetrapyrrole by the enzyme porphobilinogen deaminase. The linear tetrapyrrole is transformed into uroporphyrinogen III (URO'GEN III) by the enzyme URO'GEN III co-synthetase (Fig. 1) URO'GEN III is then sequentially decarboxylated by the enzyme uroporphyrinogen decarboxylase (UROG-D) to coproporphyrinogen III (COPRO’GEN III), in the process 7-carboxy, 6-carboxy, and 5-carboxy intermediates are formed. After passage into the mitochondrion two of the propionic acid substituents of COPRO’GEN are converted to vinyl groups, yielding protoporphyrinogen IX (PROTO’GEN IX). In the next step of the pathway six hydrogen atoms are removed from PROTO’GEN IX, with the formation of protoporphyrin IX (PROTO IX). Ferrochelatase catalyzes the final step in the pathway, viz. the insertion of ferrous iron into PROTO IX to form heme1. The heme is subsequently incorporated into several hemoproteins with cytochrome P-450 synthesis requiring more than half of the heme produced. Heme exerts feedback repression on the synthesis of ALA-S. Normally this pathway is well controlled and very little of the intermediate porphyrinogens accumulate.

Keywords

Heme Biosynthesis Free Heme Heme Moiety Heme Biosynthetic Pathway Uroporphyrinogen Decarboxylase 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    . Kappas, A., S. Sassa, K.E. Anderson. 1982. The porphyrias, In Stanbury, J.B., Wyngaarden, J.B., Fredrickson, D.S. (eds): The metabolic basis of inherited disease. New York, McGraw-Hill, p. 1301.Google Scholar
  2. 2.
    . Granick, S. 1966. The induction in vitro of the synthesis of 6- aminolevulinic acid synthetase in chemical porphyria: a response to certain drugs, sex hormones and foreign chemicals. J. Biol. Chem. 241: 1359.PubMedGoogle Scholar
  3. 3.
    . Tyrrell, D.L.J., G.S. Marks. 1972. Drug-induced porphyrin biosynthesis V. Effect of protohemin on the transcriptional and post-transcriptional phases of 6-aminolevulinic acid synthetase induction. Biochem. Pharmacol. 21: 2077.Google Scholar
  4. 4.
    . Ades, I.Z., T.M. Stevens, P.D. Drew. 1987. Biogenesis of embryonic chick delta-aminolevulinate synthase: regulation of the level of mRNA by hemin. Arch. Biochem. Biophys. 253: 297.Google Scholar
  5. 5.
    . Hamilton, J.W., W.J. Bement, P.R. Sinclair, J.F. Sinclair, K.E. Wetterhahn. 1988. Expression of 5-aminolevulinate synthase and cytochrome P-450 mRNAs in chick embryo hepatocytes in vivo and in culture. Effect of porphyrinogenic drugs and haem. Biochem. J. 255: 267.Google Scholar
  6. 6.
    . May, B.K., I.A. Borthwick, G. Srivastava, B.A. Piróla, W.H. Elliott. 1986. Control of 5-aminolevulinate synthase in animals. Curr. Topics Cell. Regul. 28: 233.Google Scholar
  7. 7.
    . Yamauchi, K., K. Hayashi, G. Kikuchi. 1980. Translocation of 6-aminolevulinate synthase from the cytosol to the mitochondria and its regulation by hemin in the rat liver. J. Biol. Chem. 255: 1746.PubMedGoogle Scholar
  8. 8.
    . Yamamoto, M., N. Hayashi, G. Kikuchi. 1983. Translational inhibition by heme of the synthesis of hepatic 6-aminolevulinate synthase in a cell-free system. Biochem. Biophys. Res. Commun. 115: 225.Google Scholar
  9. 9.
    . Badawy, A.A.B., C.J. Morgan, N.R. Davis. 1985. Tryptophan pyrrolase and the regulation of mammalian heme biosynthesis, In: Nordmann Y. (ed): Porphyrins and Porphyrias. London, John Libbey Eurotext, INSERM, p. 69.Google Scholar
  10. 10.
    . Onisawa, J., R.F. Labbe. 1963. Effects of diethyl-l,4-dihydro-2, 4,6-trimethyl-pyridine-3,5-dicarboxylate on the metabolism of porphyrins and iron. J. Biol. Chem. 238: 724.PubMedGoogle Scholar
  11. 11.
    . Tephly, T.R., A.H. Gibbs, F. DeMatteis. 1979. Studies on the mechanism of experimental porphyria produced by 3,5-diethoxy-carbonyl-1,4-dihydrocollidine. Role of a porphyrin-like inhibitor of protohaem ferrolyase. Biochem. J. 180: 241.Google Scholar
  12. 12.
    . Ortiz de Montellano, P.R., H.S. Beilan, K.L. Kunze. 1981. N-methylprotoporphyrin IX: chemical synthesis and identification as the green pigment produced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine. Proc. Natl. Acad. Sci. USA 78: 1490.PubMedCrossRefGoogle Scholar
  13. 13.
    . Ortiz de Montellano, P.R., H.S. Beilan, K.L. Kunze. 1981. N-alkylprotoporphyrin IX formation in 3,5-diethoxycarbonyl-1,4-dihydrocollidine-treated rats. J. Biol. Chem. 256: 6708.PubMedGoogle Scholar
  14. 14.
    . DeMatteis, F., A.H. Gibbs, P.B. Farmer, J.H. Lamb. 1981. Liver production of N-alkylated porphyrins caused in mice by treatment with substituted dihydropyridines. FEBS Lett. 129: 328.CrossRefGoogle Scholar
  15. 15.
    . Tephly, T.R., B.L. Coffman, G. Ingall, G.S. Abou Zeit-Har, H.D. Tabba, K.M. Smith. 1981. Identification of N-methylprotoporphyrin IX in livers of untreated mice and mice treated with 3,5-die¬thoxycarbonyl- 1,4-dihydrocollidine: source of the methyl group. Arch. Biochem. Biophys. 212: 120.Google Scholar
  16. 16.
    . Augusto, 0., H.S. Beilan, P.R. Ortiz de Montellano. 1982. The catalytic mechanism of cytochrome P-450. Spin-trapping evidence for one-electron substrate oxidation. J. Biol. Chem. 257: 11288.Google Scholar
  17. 17.
    . Mackie, J.E., G.S. Marks. Synergistic induction of 6-amino- levulinic acid synthase activity by N-ethylprotoporphyrin IX and 3,5-diethoxycarbonyl-l,4-dihydro-2,6-dimethyl-4-isobutyl-pyridine. Biochem. Pharmacol. (In press).Google Scholar
  18. 18.
    . Farrel, G.C., M.A. Correia. 1980. Structural and functional reconstitution of hepatic cytochrome P-450 in. vivo • Reversal of allylisopropylacetamide-mediated destruction of the hemoprotein by exogenous heme. J. Biol. Chem. 255: 10128.Google Scholar
  19. 19.
    . Stejskal, R., M. Itabashi, J. Stanek, Z. Hruban. 1975. Experimental porphyria induced by 3-[2-(2,4,6-trimethylphenyl)-thioethyl]-4-methylsydnone. Virchows Arch. B. Cell. Path. 18: 83.Google Scholar
  20. 20.
    . Sutherland, E.P., G.S. Marks, L.A. Grab, P.R. Ortiz de Montellano. 1986. Porphyrinogenic activity and ferrochelatase-inhibitory activity of sydnones in chick embryo liver cells. FEBS Lett. 197: 17.PubMedCrossRefGoogle Scholar
  21. 21.
    . Ortiz de Montellano, P.R., L.A. Grab. 1986. Inactivation of cytochrome P-450 during catalytic oxidation of a 3-[(arylthio) ethyl]sydnone: N-vinyl heme formation via insertion into the Fe-N bond. J. Am. Chem. Soc. 108: 5584.CrossRefGoogle Scholar
  22. 22.
    . Lukton, D., J.E. Mackie, J.E. Lee, G.S. Marks, P.R. Ortiz de Montellano. 1988. 2,2-Dialkyl-1,2-dihydroquinolines: cytochrome P-450 catalyzed N-alkylporphyrin formation, ferrochelatase inhibition, and induction of 5-aminolevulinic acid synthase activity. Chem. Res. Toxicol. 1: 208.Google Scholar
  23. 23.
    . Marks, G.S., S.A. McCluskey, J.E. Mackie, D.S. Riddick, C.A. James. 1988. Disruption of hepatic heme biosynthesis after interaction of xenobiotics with cytochrome P-450. FASEB J. 2: 2774.PubMedGoogle Scholar
  24. 24.
    . DeMatteis, F. 1978. Loss of liver cytochrome P-450 caused by chemicals. Damage to the apoprotein and degradation of the heme moiety, In: DeMatteis, F., Aldridge, W.N, (eds): Handbook of experimental pharmacology, Vol. 44. Berlin. Springer-Verlag, p. 95.Google Scholar
  25. 25.
    . Ortis de Montellano, P.R., M.A. Correia. 1983. Suicidal destruction of cytochrome P-450 during oxidative drug metabolism. Ann. Rev. Pharmacol. Toxicol. 23: 481.CrossRefGoogle Scholar
  26. 26.
    . Lyon, M.E., J.A. Owen, G.S. Marks. 1988. Xenobiotic mediated inhibition of hepatic uroporphyrinogen decarboxylase activity in 17-day-old chick embryo liver cells in culture. Biochem. Pharmacol. 37: 1123.Google Scholar
  27. 27.
    . Billi, S.C, W. De Calmanovich, L.C. San Martin de Viale. 1986. Rat liver porphyrinogen carboxylase inhibitor as a function of the degree of hexachlorobenzene-induced porphyria, In: Morris, CR., Cabrai, J.R.D. (eds): Hexachlorobenzene: proceedings of an international symposium, Vol. 77. Lyon, IARC Scientific Publications, p. 487.Google Scholar
  28. 28.
    . Cantoni, L., D. Dal Fiume, H. Rizzardini, R. Ruggieri. 1984. In vitro inhibitory effect on porphyrinogen carboxylase of liver extracts from TCDD treated mice. Toxicol. Lett. 20: 211.Google Scholar
  29. 29.
    . Smith, A.G., J.E. Francis. 1987. Chemically-induced formation of an inhibitor of hepatic uroporphyrinogen decarboxylase in inbred mice with iron overload. Biochem. J. 246: 221.PubMedGoogle Scholar
  30. 30.
    . Sinclair, P., R. Lambrecht, J. Sinclair. 1987. Evidence for a cytochrome P-450-mediated oxidation of uroporphyrinogen by cell-free extracts from chick embryos treated with 3-methylcholan-threne. Biochem. Biophys. Res. Commun. 146: 1324.Google Scholar

Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • G. S. Marks
    • 1
  • J. E. Mackie
    • 1
  • S. A. McCluskey
    • 1
  • D. S. Riddick
    • 1
  1. 1.Department of Pharmacology and ToxicologyQueen's UniversityKingstonCanada

Personalised recommendations