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. 1985 Dec;64:265–281. doi: 10.1289/ehp.8564265

Reactions of hemoglobin with phenylhydrazine: a review of selected aspects.

M D Shetlar, H A Hill
PMCID: PMC1568612  PMID: 3007094

Abstract

It is well known that phenylhydrazine induces hemolytic anemia. This is thought to result from the reaction of phenylhydrazine with hemoglobin. The accompanying oxidation of phenylhydrazine leads to the formation of a number of products, including benzene, nitrogen, hydrogen peroxide, superoxide anion and the phenyl radical. The products formed depend critically on the conditions of the experiment, especially the amount of oxygen present. It is now known that oxyhemoglobin and myoglobin react with phenylhydrazine to yield a derivative of hemoglobin containing N-phenylprotoporphyrin in which the heme group is modified. The recent identification of sigma-phenyliron(III) porphyrins in phenylhydrazine-modified metmyoglobin has aided elucidation of the mechanism of hemoglobin modification. Mechanistic schemes are proposed to account for product formation.

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Selected References

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  1. Augusto O., Kunze K. L., Ortiz de Montellano P. R. N-Phenylprotoporphyrin IX formation in the hemoglobin-phenylhydrazine reaction. Evidence for a protein-stabilized iron-phenyl intermediate. J Biol Chem. 1982 Jun 10;257(11):6231–6241. [PubMed] [Google Scholar]
  2. Augusto O., Ortiz de Montellano P. R., Quintanilha A. Spin-trapping of free radicals formed during microsomal metabolism of ethylhydrazine and acetylhydrazine. Biochem Biophys Res Commun. 1981 Aug 31;101(4):1324–1330. doi: 10.1016/0006-291x(81)91592-8. [DOI] [PubMed] [Google Scholar]
  3. BEAVEN G. H., WHITE J. C. Oxidation of phenylhydrazines in the presence of oxyhaemoglobin and the origin of Heinz bodies in erythrocytes. Nature. 1954 Feb 27;173(4400):389–391. doi: 10.1038/173389b0. [DOI] [PubMed] [Google Scholar]
  4. Beutler E. Drug-induced hemolytic anemia. Pharmacol Rev. 1969 Mar;21(1):73–103. [PubMed] [Google Scholar]
  5. COHEN G., HOCHSTEIN P. GENERATION OF HYDROGEN PEROXIDE IN ERYTHROCYTES BY HEMOLYTIC AGENTS. Biochemistry. 1964 Jul;3:895–900. doi: 10.1021/bi00895a006. [DOI] [PubMed] [Google Scholar]
  6. Castro C. E., Wade R. S., Belser N. O. Conversion of oxyhemoglobin to methemoglobin by organic and inorganic reductants. Biochemistry. 1978 Jan 24;17(2):225–231. doi: 10.1021/bi00595a005. [DOI] [PubMed] [Google Scholar]
  7. French J. K., Winterbourn C. C., Carrell R. W. Mechanism of oxyhaemoglobin breakdown on reaction with acetylphenylhydrazine. Biochem J. 1978 Jul 1;173(1):19–26. doi: 10.1042/bj1730019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Goldberg B., Stern A., Peisach J., Blumberg W. E. The detection of superoxide anion from the reaction of oxyhemoglobin and phenylhydrazine using EPR spectroscopy. Experientia. 1979 Apr 15;35(4):488–489. doi: 10.1007/BF01922723. [DOI] [PubMed] [Google Scholar]
  9. Goldberg B., Stern A., Peisach J. The mechanism of superoxide anion generation by the interaction of phenylhydrazine with hemoglobin. J Biol Chem. 1976 May 25;251(10):3045–3051. [PubMed] [Google Scholar]
  10. Goldberg B., Stern A. The generation of O2-by the interaction of the hemolytic agent, phenylhydrazine, with human hemoglobin. J Biol Chem. 1975 Mar 25;250(6):2401–2403. [PubMed] [Google Scholar]
  11. Goldberg B., Stern A. The mechanism of oxidative hemolysis produced by phenylhydrazine. Mol Pharmacol. 1977 Sep;13(5):832–839. [PubMed] [Google Scholar]
  12. Goldstein B. D., McDonagh E. M. Spectrofluorescent detection of in vivo red cell lipid peroxidation in patients treated with diaminodiphenylsulfone. J Clin Invest. 1976 May;57(5):1302–1307. doi: 10.1172/JCI108398. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gordon-Smith E. C. Drug-induced oxidative haemolysis. Clin Haematol. 1980 Oct;9(3):557–586. [PubMed] [Google Scholar]
  14. HARLEY J. D., MAUER A. M. Studies on the formation of Heinz bodies. I. Methemoglobin production and oxyhemoglobin destruction. Blood. 1960 Dec;16:1722–1735. [PubMed] [Google Scholar]
  15. Hara H., Ogawa M. Erthropoietic precursors in mice with phenylhydrazine-induced anemia. Am J Hematol. 1976;1(4):453–458. doi: 10.1002/ajh.2830010410. [DOI] [PubMed] [Google Scholar]
  16. Hill H. A., Thornalley P. J. Phenyl radical production during the oxidation of phenylhydrazine and in phenylphydrazine-induced haemolysis. FEBS Lett. 1981 Mar 23;125(2):235–238. doi: 10.1016/0014-5793(81)80727-2. [DOI] [PubMed] [Google Scholar]
  17. Hill H. A., Thornalley P. J. The effect of spin traps on phenylhydrazine-induced haemolysis. Biochim Biophys Acta. 1983 Feb 16;762(1):44–51. doi: 10.1016/0167-4889(83)90115-5. [DOI] [PubMed] [Google Scholar]
  18. Hochstein P., Jain S. K. Association of lipid peroxidation and polymerization of membrane proteins with erythrocyte aging. Fed Proc. 1981 Feb;40(2):183–188. [PubMed] [Google Scholar]
  19. Huang P. K., Kosower E. M. Complexes of phenyldiazene (phenyldiimide) with deoxyhemoglobin and ferroheme. Biochim Biophys Acta. 1968 Oct 15;165(3):483–489. doi: 10.1016/0304-4165(68)90229-8. [DOI] [PubMed] [Google Scholar]
  20. Itano H. A., Hirota K., Vedvick T. S. Ligands and oxidants in ferrihemochrome formation and oxidative hemolysis. Proc Natl Acad Sci U S A. 1977 Jun;74(6):2556–2560. doi: 10.1073/pnas.74.6.2556. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Itano H. A., Mannen S. Reactions of phenyldiazene and ring-substituted phenyldiazenes with ferrihemoglobin. Biochim Biophys Acta. 1976 Jan 14;421(1):87–96. doi: 10.1016/0304-4165(76)90172-0. [DOI] [PubMed] [Google Scholar]
  22. Itano H. A., Matteson J. L. Mechanism of initial reaction of phenylhydrazine with oxyhemoglobin and effect of ring substitutions on the biomolecular rate constant of this reaction. Biochemistry. 1982 May 11;21(10):2421–2426. doi: 10.1021/bi00539a022. [DOI] [PubMed] [Google Scholar]
  23. JANDL J. H., ENGLE L. K., ALLEN D. W. Oxidative hemolysis and precipitation of hemoglobin. I. Heinz body anemias as an acceleration of red cell aging. J Clin Invest. 1960 Dec;39:1818–1836. doi: 10.1172/JCI104206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Mansuy D., Battioni P., Mahy J. P., Gillet G. Comparison of the hemoglobin reactions with methyl- and phenyl-hydrazine; intermediate formation of a hemoglobin Fe-(II)-methyldiazene complex. Biochem Biophys Res Commun. 1982 May 14;106(1):30–36. doi: 10.1016/0006-291x(82)92053-8. [DOI] [PubMed] [Google Scholar]
  25. Misra H. P., Fridovich I. The oxidation of phenylhydrazine: superoxide and mechanism. Biochemistry. 1976 Feb 10;15(3):681–687. doi: 10.1021/bi00648a036. [DOI] [PubMed] [Google Scholar]
  26. Ortiz de Montellano P. R., Kerr D. E. Inactivation of catalase by phenylhydrazine. Formation of a stable aryl-iron heme complex. J Biol Chem. 1983 Sep 10;258(17):10558–10563. [PubMed] [Google Scholar]
  27. ROSTORFER H. H., CORMIER M. J. The formation of hydrogen peroxide in the reaction of oxyhemoglobin with methemoglobin-forming agents. Arch Biochem Biophys. 1957 Sep;71(1):235–249. doi: 10.1016/0003-9861(57)90025-5. [DOI] [PubMed] [Google Scholar]
  28. ROSTORFER H. H., TOTTER J. R. The reduction of methemoglobin by phenylhydrazine under anaerobic conditions. J Biol Chem. 1956 Aug;221(2):1047–1055. [PubMed] [Google Scholar]
  29. Saito S., Itano H. A. beta-meso-Phenylbiliverdin IX alpha and N-phenylprotoporphyrin IX, products of the reaction of phenylhydrazine with oxyhemoproteins. Proc Natl Acad Sci U S A. 1981 Sep;78(9):5508–5512. doi: 10.1073/pnas.78.9.5508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Uyeda M., Peisach J. Ultraviolet difference spectroscopy of myoglobin: assignment of pK values of tyrosyl phenolic groups and the stability of the ferryl derivatives. Biochemistry. 1981 Mar 31;20(7):2028–2035. doi: 10.1021/bi00510a045. [DOI] [PubMed] [Google Scholar]

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