Skip to main content
PMC home page
Journal of Clinical Pathology logoLink to Journal of Clinical Pathology
. 1989 Sep;42(9):977–981. doi: 10.1136/jcp.42.9.977

Effect of isoniazid, a haem inhibitor, on globin chain synthesis in reticulocytes from non-thalassaemic and beta thalassaemic subjects.

G Chalevelakis 1, A G Yalouris 1, C Lyberatos 1, T Economopoulos 1, C Anastasiou 1, J Hatziioannou 1, S Raptis 1
PMCID: PMC501799  PMID: 2794087

Abstract

The effect of isonicotinic acid hydrazide (INH), a potent haem inhibitor, on globin chain synthesis was studied in reticulocytes from the following groups of patients: four non-thalassaemic patients (group i); five beta thalassaemia heterozygotes (group ii); three Hb S/beta thalassaemia heterozygotes (group iii); and two additional patients--one with homozygous beta thalassaemia and the other with thalassaemia intermedia (group iv). This was done to determine whether haem inhibitors depress alpha globin chain synthesis. The progressive increase of INH concentration (10-40 mmol l-1) in reticulocytes from a beta thalassaemia heterozygote resulted in a remarkable decrease of the alpha and beta chain synthesis, ranging from 80% to 97% and from 74% to 96% of control values, respectively, and in a gradual drop of alpha:beta ratio from 1.87 to 1.38. Furthermore, in the samples incubated with 40 mmol l-1 INH, a pronounced inhibition of globin chain synthesis 77 (19%) for alpha chain and 67 (27%) for beta or beta S chain) and a substantial drop of the alpha:beta or beta S ratio in samples with INH (median 1.16) compared with that in samples without INH (median 1.70) were observed. The inhibitory effect of INH was significantly or completely corrected by adding exogenous haem. It is suggested that haem inhibition and the resulting preferential diminution of alpha chain synthesis could provide a new approach to the treatment of homozygous beta thalassaemia with an excess of detrimental free alpha chain in erythroid cells.

Full text

PDF
977

Selected References

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

  1. Adams J. G., 3rd, Newman M. V., Steinberg M. H., DeSimone J. Effect of lead and ethanol upon gamma-globin synthesis in sickle reticulocytes. Am J Med Sci. 1986 Nov;292(5):299–305. doi: 10.1097/00000441-198611000-00009. [DOI] [PubMed] [Google Scholar]
  2. Adamson S. D., Herbert E., Kemp S. F. Effects of hemin and other porphyrins on protein synthesis in a reticulocyte lysate cell-free system. J Mol Biol. 1969 Jun 14;42(2):247–258. doi: 10.1016/0022-2836(69)90041-2. [DOI] [PubMed] [Google Scholar]
  3. BIEHL J. P., VILTER R. W. Effects of isoniazid on pyridoxine metabolism. J Am Med Assoc. 1954 Dec 25;156(17):1549–1552. doi: 10.1001/jama.1954.02950170003002. [DOI] [PubMed] [Google Scholar]
  4. Chalevelakis G., Clegg J. B., Weatherall D. J. Globin synthesis in normal human bone marrow. Br J Haematol. 1976 Dec;34(4):535–557. doi: 10.1111/j.1365-2141.1976.tb03600.x. [DOI] [PubMed] [Google Scholar]
  5. Chalevelakis G., Clegg J. B., Weatherall D. J. Imbalanced globin chain synthesis in heterozygous beta-thalassemic bone marrow. Proc Natl Acad Sci U S A. 1975 Oct;72(10):3853–3857. doi: 10.1073/pnas.72.10.3853. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Clegg J. B., Naughton M. A., Weatherball D. J. Abnormal human haemoglobins. Separation and characterization of the alpha and beta chains by chromatography, and the determination of two new variants, hb Chesapeak and hb J (Bangkok). J Mol Biol. 1966 Aug;19(1):91–108. doi: 10.1016/s0022-2836(66)80052-9. [DOI] [PubMed] [Google Scholar]
  7. FESSAS P. Inclusions of hemoglobin erythroblasts and erythrocytes of thalassemia. Blood. 1963 Jan;21:21–32. [PubMed] [Google Scholar]
  8. FESSAS P., LOUKOPOULOS D. ALPHA-CHAIN OF HUMAN HEMOGLOBIN: OCCURRENCE IN VIVO. Science. 1964 Feb 7;143(3606):590–591. doi: 10.1126/science.143.3606.590. [DOI] [PubMed] [Google Scholar]
  9. Franco R. S., Hogg J. W., Martelo O. J. The effect of INH-inhibited heme synthesis on globin synthesis. J Lab Clin Med. 1979 Apr;93(4):679–686. [PubMed] [Google Scholar]
  10. Freedman M. L., Cohen H. S., Rosman J., Forte F. J. Ethanol inhibition of reticulocyte protein synthesis: the role of haem. Br J Haematol. 1975 Jul;30(3):351–363. doi: 10.1111/j.1365-2141.1975.tb00551.x. [DOI] [PubMed] [Google Scholar]
  11. Fuhr J. E., Gengozian N. Coordination of heme and globin synthesis in primate reticulocytes. Biochim Biophys Acta. 1973 Aug 17;320(1):53–58. doi: 10.1016/0304-4165(73)90164-5. [DOI] [PubMed] [Google Scholar]
  12. Giglioni B., Gianni A. M., Comi P., Ottolenghi S., Rungger D. Translational control of globin synthesis by haemin in Xenopus oocytes. Nat New Biol. 1973 Nov 28;246(152):99–102. doi: 10.1038/newbio246099a0. [DOI] [PubMed] [Google Scholar]
  13. Grayzel A. I., Hörchner P., London I. M. The stimulation of globin synthesis by heme. Proc Natl Acad Sci U S A. 1966 Mar;55(3):650–655. doi: 10.1073/pnas.55.3.650. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Legon S., Jackson R. J., Hunt T. Control of protein synthesis in reticulocyte lysates by haemin. Nat New Biol. 1973 Jan 31;241(109):150–152. doi: 10.1038/newbio241150a0. [DOI] [PubMed] [Google Scholar]
  15. Maxwell C. R., Rabinovitz M. Evidence for an inhibitor in the control of globin synthesis by hemin in a reticulocyte lysate. Biochem Biophys Res Commun. 1969 Apr 10;35(1):79–85. doi: 10.1016/0006-291x(69)90485-9. [DOI] [PubMed] [Google Scholar]
  16. Nathan D. G., Gunn R. B. Thalassemia: the consequences of unbalanced hemoglobin synthesis. Am J Med. 1966 Nov;41(5):815–830. doi: 10.1016/0002-9343(66)90039-8. [DOI] [PubMed] [Google Scholar]
  17. Peters R. E., May A., Jacobs A. Globin chain synthesis ratios in sideroblastic anaemia. Br J Haematol. 1983 Feb;53(2):201–209. doi: 10.1111/j.1365-2141.1983.tb02012.x. [DOI] [PubMed] [Google Scholar]
  18. Ponka P., Neuwirt J. The use of reticulocytes with high non-haem iron pool for studies of regulation of haem synthesis. Br J Haematol. 1970 Nov;19(5):593–604. doi: 10.1111/j.1365-2141.1970.tb01643.x. [DOI] [PubMed] [Google Scholar]
  19. Weatherall D. J., Clegg J. B., Na-Nakorn S., Wasi P. The pattern of disordered haemoglobin synthesis in homozygous and heterozygous beta-thalassaemia. Br J Haematol. 1969 Mar;16(3):251–267. doi: 10.1111/j.1365-2141.1969.tb00400.x. [DOI] [PubMed] [Google Scholar]
  20. White J. M., Ali M. A. Globin synthesis in sideroblastic anaemia. II. The effect of pyridoxine, -aminolaevulinic acid and haem, in vitro. Br J Haematol. 1973 Apr;24(4):481–489. doi: 10.1111/j.1365-2141.1973.tb01674.x. [DOI] [PubMed] [Google Scholar]
  21. White J. M., Brain M. C., Ali M. A. Globin synthesis in sideroblastic anaemia. I. Alpha and beta peptide chain synthesis. Br J Haematol. 1971 Mar;20(3):263–275. doi: 10.1111/j.1365-2141.1971.tb07037.x. [DOI] [PubMed] [Google Scholar]
  22. White J. M., Harvey D. R. Defective synthesis of and globin chains in lead poisoning. Nature. 1972 Mar 10;236(5341):71–73. doi: 10.1038/236071a0. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Pathology are provided here courtesy of BMJ Publishing Group

RESOURCES