title: Ligands and oxidants in ferrihemochrome formation and oxidative hemolysis.
abstract: We have investigated the effect of size of a single neutral ring substituent on the induction of hemolytic anemia and the formation of a ferrihemochrome by substituted phenylhydrazines. The severity of induced anemia decreased with increase in size of a halogen atom or an alkyl group ortho to the hydrazino group, little anemia resulting from 2-iodophenylhydrazine and no anemia from 2-tert-butylphenylhydrazine. The size of a halogen atom or an alkyl group at the meta or para position had relatively little effect on the severity of induced anemia. The ability of an arylhydrazine to induce hemolytic anemia paralleled its ability to produce a ferrihemochrome with an exogenous ligand, probably the corresponding aryldiazene. In general, rapid and complete formation of ferrihemochrome occurred with arylhydrazines that induced severe anemia. The degree of hemolysis induced by an arylhydrazine was not related to its rate of autooxidation, i.e., the rate at which oxidants are formed by the reduction of oxygen. We propose a mechanism of arylhydrazine-induced oxidative denaturation based on the simultaneous formation of hydroxyl radical and aryldiazene ferrihemochrome in a reaction of oxyhemoglobin with arylhydrazine. We suggest that after oxidation of the porphyrin ring is initiated by a hydroxyl radical, oxidative cleavage of the ring is facilitated by the presence of a large ligand in the heme crevice. Thus, aryldiazene ferrihemochrome may contribute to instability in a hemoglobin molecule, whereas globin ferrihemochrome results from instability.
mesh_terms: D000743:Anemia, Hemolytic / Q000097:blood* / Q000139:chemically induced; D000818:Animals; D001772:Blood Cell Count; D006400:Hematocrit; D007700:Kinetics; D008024:Ligands; D008706:Methemoglobin / Q000378:metabolism*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000097:blood; D010659:Phenylhydrazines; D011485:Protein Binding; D011817:Rabbits; D012156:Reticulocytes / Q000502:physiology; D013053:Spectrophotometry; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D010659:Phenylhydrazines; D008706:Methemoglobin; D010100:Oxygen
references.citation: Biochem Biophys Res Commun. 1975 Feb 3;62(3):561-7
references.pmid: 1120068
references.citation: Blood. 1961 Apr;17:418-33
references.pmid: 13711607
references.citation: J Mol Biol. 1964 Jan;8:96-104
references.pmid: 14149967
references.citation: Br J Haematol. 1976 Jan;32(1):99-104
references.pmid: 1259930
references.citation: J Chem Soc Perkin 1. 1972;20:2540-8
references.pmid: 4674785
references.citation: Pharmacol Rev. 1969 Mar;21(1):73-103
references.pmid: 4887725
references.citation: Proc Soc Exp Biol Med. 1974 Dec;147(3):656-8
references.pmid: 4445150
references.citation: Prog Hematol. 1971;7(0):69-109
references.pmid: 4950839
references.citation: Proc R Soc Lond B Biol Sci. 1969 May 20;173(1031):113-40
references.pmid: 4389425
references.citation: Biochemistry. 1976 Feb 10;15(3):681-7
references.pmid: 175827
references.citation: Semin Hematol. 1969 Apr;6(2):116-32
references.pmid: 4890092
references.citation: J Mol Biol. 1976 Jul 5;104(3):707-22
references.pmid: 950675
references.citation: Medicine (Baltimore). 1955 May;34(2):131-92
references.pmid: 14383004
references.citation: Proc Natl Acad Sci U S A. 1970 Oct;67(2):485-92
references.pmid: 5289003
references.citation: Biochem Soc Trans. 1976;4(2):209-14
references.pmid: 1001644
references.citation: J Biol Chem. 1971 May 25;246(10):3356-66
references.pmid: 4324898
references.citation: Biochem J. 1976 Jun 1;155(3):493-502
references.pmid: 182128
references.citation: J Mol Biol. 1976 Jul 5;104(3):687-706
references.pmid: 950674
references.citation: Br J Haematol. 1975 Jul;30(3):259-64
references.pmid: 172110
references.citation: Blood. 1968 Jun;31(6):766-77
references.pmid: 4871702
references.citation: Biochim Biophys Acta. 1976 Jan 14;421(1):87-96
references.pmid: 1247590
references.citation: Blood. 1965 Oct;26(4):433-48
references.pmid: 5825007
references.citation: Nature. 1954 Feb 27;173(4400):389-91
references.pmid: 13144768
references.citation: Blood. 1968 Jun;31(6):778-90
references.pmid: 5654969
references.citation: Biochim Biophys Acta. 1975 Jun 26;393(2):404-18
references.pmid: 167836
references.citation: Biochemistry. 1964 Jul;3:895-900
references.pmid: 14214074
references.citation: Nature. 1975 Aug 21;256(5519):665-7
references.pmid: 1153002
references.citation: Br J Haematol. 1974 Apr;26(4):513-7
references.pmid: 4367628
references.citation: Biochem Biophys Res Commun. 1974 Apr 23;57(4):1104-10
references.pmid: 4830750
references.citation: Blood. 1968 Mar;31(3):388-95
references.pmid: 5640633
references.citation: Biochem Pharmacol. 1968 Mar;17(3):423-7
references.pmid: 4173613
references.citation: Acta Haematol. 1962;27:321-33
references.pmid: 13868714
references.citation: Ann N Y Acad Sci. 1975 Apr 15;244:533-52
references.pmid: 1094885
references.citation: J Clin Invest. 1960 Dec;39:1818-36
references.pmid: 13789379
references.citation: J Am Chem Soc. 1975 Sep 17;97(19):5363-9
references.pmid: 1159229
references.citation: J Biol Chem. 1975 Mar 25;250(6):2401-3
references.pmid: 163828
references.citation: J Biol Chem. 1976 May 25;251(10):3045-51
references.pmid: 5452
references.citation: Arch Biochem Biophys. 1957 Sep;71(1):235-49
references.pmid: 13459445
references.citation: FEBS Lett. 1969 Nov 29;5(4):295-298
references.pmid: 11947301
references.citation: Nature. 1968 Aug 31;219(5157):902-9
references.pmid: 5691676